Pyrimidin derivatives

ABSTRACT

The invention relates to new pharmaceutically active compounds which are are P2-purinoceptor 7-transmembrane (TM) G-protein coupled receptor antagonists, compositions containing them and processes for their preparation.

This application is a 371 of PCT/SE98/01391 filed Jul. 15, 1998.

The invention provides new pharmaceutically active compounds,composition containing them and processes for their preparation. Thecompounds are useful in therapy because they are P2-purinoceptor7-transmembrane (TM) G-protein coupled receptor antagonists.

ATP receptors have been shown to be present on a wide number ofdifferent cell types (Dubyak et al Am J Physiol (1993) 265, C577-C606).Neutrophils, monocytes and macrophages have been isolated from severalspecies including humans and ATP and/or UTP have been shown to increaseintracellular calcium levels. Activation of these receptors onleukocytes can either directly stimulate certain types of inflammatoryresponse or can prime the effector cells to other inflammatory mediatorsin vivo. ATP can upregulate the expression of adhesion molecules (Freyeret al J Immun. (1988) 141, 580-586) which causes enhanced adhesion ofcirculating leukocytes to endothelial cells and their enhanced migrationinto the tissue space. ATP has also been shown to promote chemotaxis ofboth eutrophils and eosinophils (Verghese et al J. B. C. (1996) 271,15597-15601 and Burders et al Blood (1993) 81, 49-55) which may promotean inflammatory response. ATP priming of neutrophils can also potentiatesuperoxide production (Seifert et al Eur J Biochem (1989) 181, 277-285).ATP receptors are also present on a number of other cell types such aschondrocytes, keratinocytes, microglia and goblet cells (Leong et al BBA(1994) 1201, 298-304; Pillai et al J Clin Invest (1992) 90, 42-51; Walzet al J Neuroscience (1993) 13, 4403-4411 and Abdullah et al Biochem J(1996) 316, 943-951). Stimulation of the receptors on these cells canstimulate or enhance inflammatory responses and antagonist of thereceptor may therefore be of use in a number of inflammatory diseasessuch as asthma, inflammatory bowel disease, ARDS, psoriasis, rheumatoidarthritis, myocardial ischaemia, COPD, cystic fibrosis,arthereosclerosis, restenosis, peridontal disease, septic shock,osteoarthritis and stroke. ATP receptors have also been reported ontumour cells (Dubyak et al J. Biol. Chem., (1985) 260, 10653-10661 andWagner et al Gastroenterolgy, (1997), 112(4) suppl. page A1198) and maybe involved in the development of cancer. Antagonists may therefore beuseful in treatment of cancer.

According to the invention there is provided a compound of formula (I)or salts thereof:

in which:

X is a bond, CH₂ or a C₁₋₃alkylene group optionally interrupted byoxygen;

R is hydrogen, NO₂, NH₂, N(C₁₋₆alkyl)₂, CO₂H, CH₂OH, halogen,CO₂C₁₋₆alkyl, C₁₋₈alkyl optionally interrupted by one or more oxygen,nitrogen or sulphur atoms and optionally substituted by CO₂H, or R ishydroxy, phenyl optionally substituted by CH₂CO₂H, or CONR³R⁴ where R³and R⁴ are independently hydrogen, C₁₋₆alkyl optionally substituted byhydroxy or CO₂H and/or optionally interrupted by oxygen, nitrogen orsulphur;

R¹ is NR⁵R⁶ or CH₂NR⁵R⁶ where R⁵ and R⁶ are independently hydrogen,CH₂CO₂H, CHPh₂ or C(=S)CH₂CH₂CO₂H, or R¹ is CH₂NR⁷CH₂CO₂H where R⁷ ishydrogen, C₁₋₆ alkyl or CO₂CH₂Ph, or R¹ is C₁₋₈alkyl optionallyinterrupted by one or more oxygen, nitrogen or sulphur atoms andoptionally substituted by CO₂H, or R¹ is R⁸-PO(OH)₂, or -R⁸tetrazol-5-ylwhere R⁸ is a bond, OCH₂, SCH₂, CONH, CONHCH₂, CONHCH₂CONH, NHCH₂CONHNHCH(R³), NR⁹(CH₂)q where R⁹ is hydrogen or C₁₋₆alkyl and q is 1 or 2 orR²⁰—CO₂H where R²⁰ is a bond, CONHCH₂ or NHCH(R³) where R³ is as definedabove or R¹ is a group of formula (i):

where B is a 4-, 5-, or 6 membered saturated ring containing a nitrogenatom optionally substituted by hydroxy and substituted by CO₂H orCONH-Het where Het is tetrazol-5-yl, or a thiazole or thiadiazole ringsubstituted by CO₂H or CH₂CO₂H, or B is phenyl or a 5-membered aromaticheterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen,oxygen or sulphur optionally substituted by one or more groups selectedfrom CF₃, or CO₂H, CH₂OH, C₁₋₆alkyl optionally interrupted by one ormore oxygen atoms, CH₂CH₂CO₂H, C(CO₂H)═N—OMe, tetrazol-5-yl orCH₂tetrazol-5-yl; and

R¹⁰ is a bond, sulphur atom, —CONH—, CH₂CH₂O, a group—NR¹¹—CH(CO₂H)—CH₂—, or a group CONR¹¹(CH₂)_(p)CONR¹²— or—NR¹¹—(CH₂)_(p)—CONR¹²— where R¹¹ and R¹² are independently hydrogen orC₁₋₆alkyl and p is a 1 or 2;

R² is a group of formula (ii) or (iii):

where R¹³ groups are independently hydrogen, halogen, methoxy,methylthio or C₁₋₂alkyl (optionally substituted by one or more fluorineatoms);

R¹⁴ groups are independently hydrogen, halogen, hydroxy, C₁₋₃alkylthio,C₁₋₄alkyl (optionally substituted by one or more fluorine atoms),C₃₋₄cycloalkyl, MeOCH₂, MeSCH₂ or C₁₋₂alkoxy;

R¹⁵ groups are independently hydrogen, halogen or methyl (optionallysubstituted by one or more fluorine atoms);

Z¹ CH═CH, CF═CH or CF═CF;

Z² is a single bond, oxygen, sulphur, CH₂CH═CH, CH₂CH═CHCH₂ orC₁₋₄alkylene group optionally interrupted by an oxygen or sulphur atom;

R¹⁶ are independently hydrogen, halogen, C₁₋₂alkyl, CF₃ or a methylthiogroup or hydroxy;

Q¹ and Q² each independently represent an O or S;

or a salt thereof,

provided that when Q¹ is oxygen, R² is a group of formula (ii).

Alkyl groups, whether alone or as part of another group, can be straightchain or branched. Unless stated otherwise, the term alkyl as usedherein refers to C₁₋₆alkyl groups, such as methyl, ethyl, propyl andbutyl groups.

Certain compounds of formula (I) are capable of existing insteroisomeric forms including enantiomers and the invention extends toeach of these stereoisomeric forms and to mixtures thereof includingracemates. The different stereoisomeric forms may be separated one fromthe other by the usual methods, or any given isomer may be obtained bysterospecific or asymmetric synthesis. The invention also extends to anytautomeric forms and mixtures thereof.

Suitably X is a bond, CH₂ or a C₁₋₃alkylene group optionally interruptedby oxygen.

Preferably X is CH₂, a bond or CH₂CH₂O, more preferably X is CH₂.

Suitably R is hydrogen, NO₂, NH₂, N(C₁₋₆alkyl)₂, CO₂H, CH₂OH, halogen,CO₂C₁₋₆alkyl, C₁₋₈alkyl optionally interrupted by one or more oxygen,nitrogen or sulphur atoms and optionally substituted by CO₂H, or R ishydroxy, phenyl optionally substituted by CH₂CO₂H, or CONR³R⁴ where R³and R⁴ are independently hydrogen, C₁₋₆alkyl optionally substituted byhydroxy or CO₂H and/or optionally interrupted by oxygen, nitrogen orsulphur. Preferably R is meta or para relative to the X group. PreferredR groups includes hydrogen, C₁₋₆alkoxy, C₁₋₈alkyl optionally interruptedby one or two oxygen atoms and optionally substituted by CO₂H, CH₂OH,hydroxy and halogen. More preferably R is hydrogen, methoxy,CH₂OCH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂OH, CH₃, hydroxy, OCH₂CO₂H orO(CH₂)₃CO₂H.

Suitably R¹ is NR⁵R⁶ or CH₂NR⁵R⁶ where R⁵ and R⁶ are independentlyhydrogen, CH₂CO₂H, CHPh₂ or C(═S)CH₂CH₂CO₂H, or R¹ is CH₂NR⁷CH₂CO₂Hwhere R⁷ is hydrogen, C₁₋₆alkyl or CO₂CH₂Ph, or R¹ is C₁₋₈alkyloptionally interrupted by one ore more oxygen, nitrogen or sulphur atomsand optionally substituted by CO₂H, or R¹ is —R⁸—PO(OH)₂, or —R⁸-tetrazol-5-yl where R⁸ is a bond, OCH₂, SCH₂, CONH, CONHCH₂,CONHCH₂CONH, NHCH₂CONH, NHCH(R³) or —R⁸—CO₂H where R⁸ is a bond, CONHCH₂NHCH(R³) where R³ is as defined above or R⁸ is NR⁹(CH₂)_(q) where R⁹ ishydrogen or C₁₋₆alkyl and q is 1 or 2, or R¹ is a group of formula (i)as defined above.

When X is CH₂, R¹ is preferably meta or para with respect to the Xlinkage. Preferably R¹ is CO₂H, —PO(OH)₂, C₁₋₈alkyl optionallyinterrupted by one or two oxygen atoms and optionally substituted byCO₂H, or R¹ is a group of formula (i) where B is phenyl, thiazole,pyrazole optionally substituted by CO₂H or C₁₋₆alkyl optionallyinterrupted by one or two oxygen atoms, or R¹ is NR⁵R⁶ or CH₂NR⁵R⁶ whereR⁵ and R⁶ are independently, CH₂CO₂H, CHPh₂ or C(═S)CH₂CH₂CO₂H, or R¹ isCH₂NR⁷CH₂CO₂H where R⁷ is CO₂CH₂Ph.

Suitably R² is a group of formula (ii) or (iii) as defined above.Preferably R² is a group of formula (ii) where Z¹ is CH═CH. PreferablyR¹³, R¹⁴ and R¹⁵ are all hydrogen.

Suitably Q¹ and Q² each independently represent an O or S. Preferably Q¹is S and Q² is O or S.

Particularly preferred compounds of the invention include:

3-[[5-[9H-Fluoren-9-yl]-3,4-dihydro-2-oxo-2-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzeneaceticacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzenephosphonicacid,

5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2oxo-4thioxo-1-(2H)-pyrimidinyl]methyl]-2-methoxybenzoicacid,

2-[3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]-4-thiazolecarboxylicacid,

3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[2-methoxyethoxymethyl]benzoicacid,

3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[phenoxymethyl]benzoicacid,

3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5[ethoxymethyl]benzoicacid,

1-[[3-[[3-Carboxy-5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-4-pyrazolecarboxylicacid,

3-[[3-[[3-Carboxy-5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methoxy]-5-ethoxybenzoicacid,

3-[[3-Carboxy-5[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methoxy]-5-[2-methoxyethoxy]benzoicacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[hydroxymethyl]benzoicacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methylbenzoicacid,

5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-hydroxybenoicacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenoxy]aceticacid,

2-Bromo-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2oxo-4thioxo-1-(2H)-pyrimidinyl]methyl]-benzoicacid,

5-[[-5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-[phenylmethyl]benzoicacid,

2-Butyl-5-[[5-{5-H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,

4-[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]benzoicacid,

5-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl-1,3-bis[oxyaceticacid],

4-[3-[Carboxymethoxy]-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]oxybutanoicacid,

3-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl][carboxymethyl]amino]-3-thioxobutanoicacid,

N-[[3-[[5-{5-Dibenzo-[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-N-[phenylmethoxycarbonyl]glycine,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[[carboxymethyl][diphenylmethyl]amino]benzoicacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[carboxymethylamino]benzoicacid,

2-[2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid,

2-[Carboxymethoxy]-6-[2-[50{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid,

4-[2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]-1,3-benzenedioicacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dithioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,

3-[[5-{5H-Dibenzo[a,d]cyclohepton-5-yl}-3,4-dihydro-4-oxo-2-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,

and pharmaceutically acceptable salts thereof.

In a further aspect the invention provides a process for the preparationof a compound of formula (I) which comprises reacting a compound offormula (II):

where Q¹, Q² and R² are as defined in formula (I) or are protectedderivatives thereof with a compound of formula (III):

where R, R¹ and X are as defined in formula (I) or are protectedderivatives thereof and L is a leaving group, and optionally thereafterin any order:

removing any protecting groups

converting the compound of formula (I) into a further compound offormula (I)

forming a salt

Reaction of compounds of formulae (II) and (III) can be carried out inthe presence of a suitable base, for example a metal carbonate such aspotassium carbonate or cesium carbonate in a suitable polar solvent suchas dimethylformamide or dimethylsulphoxide at 10° C. to 80° C.Preferably L is halogen, in particular bromo. Alternatively the compoundof formula (II) can be silylated with a suitable silating reagent suchas a trialkylsilychloride and/or 1,1,1,3,3,3-hexamethyldisilazane in asuitable solvent such as pyridine, toluene or 1,4-dioxane at atemperature of about 80° C. to about 140° C. followed by addition of thecompound of formula (III) in a suitable solvent such as acetonitrile atelevated temperature, for example at reflux. We prefer to silylate usingbis(trimethylsilyl)trifluoroacetamide in refluxing 1,2-dichloroethanefollowed by treatment with the appropriate compound of formula (III)(where L is halogen, preferably bromide or chloride) in acetonitrile and1,2-dichloroethane at reflux.

It will be appreciated by those skilled in the art that in the processdescribed above the functional groups of intermediate compounds may needto be protected by protecting groups.

Functional groups of which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude organosilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydro-pyranyl. Suitable protecting groups for amino includetert-butoxycarbonyl or benzyloxy carbonyl. Suitable protecting groupsfor carboxylic acid include C₁₋₆alkyl or benzyl esters. The protectionand deprotection of functional groups may take place before or after areaction step.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’, 2nd edition, T. W. Greene & P.G. M. Wutz, Wiley-Interscience (1991).

In particular compounds of formula (III) where R and R¹ contains acarboxylic acid group can be protected as esters, particularly asC₁₋₆alkyl esters. Basic hydrolysis of such esters can be performed usingmetal hydroxides or quaternary ammonium hydroxides such as sodiumhydroxide in a solvent such as an aqueous alcohol, 1,4-dioxane,tetrahydrofuran or dimethylformamide at a temperature between 10° C. and100° C. Where Q¹/Q² are oxygen, acidic hydrolysis may also be performedusing mineral acid such as HCl or a strong organic acid such astrifluoroacetic acid in a suitable solvent such as 1,4-dioxane. Weprefer basic hydrolysis using lithium hydroxide in aqueous methanol atambient temperature.

Compounds of formula (I) where R or R¹ is a carboxylic acid can bereacted with an appropriate amine and converted to further compounds offormula (I) using standard methods employed in peptide synthesis, forexample using a coupling agent. Coupling agents which may be usedinclude 1,1′-carbonyldiimidazole and 1,3-dicyclohexylcarbodiimide in asuitable solvent such as dimethylformamide, dichloromethane,tetrahydrofuran or acetonitrile at about 0° C. to about 30° C. We preferto use bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate with atrialkylamine such as N,N-diisopropylethylamine and4-dimethylaminopyridine in dimethylformamide at ambient temperature.

Compounds of formula (I) where Q¹ is oxygen can be converted to acorresponding compound of formula (I) where Q¹ is sulphur using standardthiation conditions for conversion of uridine and thymidine nucleosidesinto their corresponding thio-nucleoside derivatives (see “Chemistry ofNucleosides and Nucleotides” edited by Leroy B. Townsend, Plenum Pressvolume 1). Thiation may be achieved using reagents such as diphosphoruspentasulphide or Lawesson's reagent in a solvent such as pyridine,1,4-dioxane, toluene, xylene, or tetrahydrofuran at a temperature ofabout 50° C. to about 130° C. We prefer to use Lawesson's reagent in1,4-dioxane at about 100° C.

Compounds of formula (I) where Q² is S can be prepared from compoundswhere Q² is O and Q¹ is S. The 4-thioxo group can be alkylated bytreatment with a metal bicarbonate or carbonate and an alkyl halide inan appropriate solvent such as an aqueous alcohol at a temperature of10° C. to 70° C. We prefer to use sodium bicarbonate and methyl iodidein aqueous methanol at 40° C. The 2-position of the uracil can bethiated using the conditions described above, preferably usingLawesson's reagent at 100° C. Treatment of this product with H₂S in atrialkylamine, preferably triethylamine, in pyridine at ambienttemperature gives the target compound where Q¹ is S and Q² is S.Alternatively the 4-alkylthio compound can be hydrolysed to compounds offormula (I) where Q² is S and Q¹ is O by treatment with HCl in aqueousalcohol at a temperature of 60-100° C. preferably with 2M HCl in aqueousethanol at reflux.

Compounds of formula (II) where Q¹ and Q² are oxygen can be prepared byreaction of a compound of formula (IV):

where R¹⁷ and R¹⁸ are independently C₁₋₆alkyl or benzyl with a compoundof formula (V) or (VI):

where Z¹, Z², R¹³, R¹⁴, R¹⁵ and R¹⁶ are as defined in formula (I)followed by reduction of the resulting alcohol. Compounds of formula(IV) are prepared by treating the corresponding halide with an alkyllithium reagent (alkyl=n-Butyl, sec-Butyl, tert-Butyl) in solvents suchas tetrahydrofuran or diethyl ether at low temperature e.g. −40° C. to−78° C.

The resulting alcohol can then be reduced and deprotected to compoundsof formula (II) by treatment with a trialkylsilane such astriethylsilane in a suitable solvent such as dichloromethane, chlorform,or 1,2-dichloroethane and an acid or Lewis acid such as trifluoroaceticacid or borontrifluoride diethyl ether complex. We preferred to performthe metal halogen exchange on5-bromo-2,4-bis(1,1-dimethylethoxy)pyrimidine using n-butyllithium atabout −78° C. in tetrahydrofuran.

When the lithio species is quenched with a substituted10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one the resulting substituted10,11-dihydro-5-(2,4-bis(alkoxy)pyrimidin-5-yl)-5H-dibenzo[a,d]cyclohepten-5-olcan then be converted to the uracil (II) (where Z¹ is CH═CH) byrefluxing in a carboxylic acid solvent (Chem. Ber., 1989, 122, 1595). Weprefer to use acetic acid. In some cases further treatment withtrifluoroacetic acid at reflux may be required for the dehydration togive the substituted uracil (II).

Compounds of formula (II) can also be prepared from uracil and theappropriately substituted 5H-dibenzo[a,d]cyclohepten-5-ol by refluxingin a carboxylic acid solvent such as acetic acid (J. Org. Chem., 1974,39, 587).

Compounds of formula (III) where X is CH₂ can be prepared from compoundsof formula (VII):

where R and R¹ are as defined in formula (I) by treating with, forexample, a halogenating agent. Suitable reagents includeN-bromosuccinimide in a suitable solvent such as chloroform,dichloromethane, ethyl acetate or benzene at elevated temperature andirradiated with strong light. Preferably the reaction is carried out inthe presence of a catalytic amount of benzoyl peroxide at reflux andirradiated with a 500W halogen lamp.

Compounds of formula (I) in which X is a bond can be prepared byreacting compounds of formula (II) with compounds of formula (VIII):

where R and R¹ are as defined in formula (I). The reaction can becarried out in the presence of a suitable base, for example a metalcarbonate such as cesium carbonate in a suitable polar solvent such asdimethylformamide or dimethylsulphoxide at about 50-130° C. Preferablythe reaction is carried out using cesium carbonate in dimethylformamideat about 100° C.

Salts of the compounds of formula (I) may be formed by reacting the freeacid, or a salt thereof, with one or more equivalents of the appropriatebase (for example ammonium hydroxide optionally substituted by C₁₋₆alkylor an alkali metal or alkaline earth metal hydroxide). The reaction maybe carried out in a solvent or medium in which the salt is insoluble orin a solvent in which the salt is soluble, e.g. water, alcohol oracetone, which may be removed in vacuo, or by freeze drying. Thereaction may also be a metathetical process or it may preferably becarried out on an ion exchange resin. The non-toxic pharmaceuticallyacceptable salts are preferred although other salts may be useful, e.g.in isolating or purifying the product.

Novel intermediate form a further aspect of the invention.

The compound of the invention have been submitted to the assay outlinedbelow and have been found to be P2 7-TM G-protein receptor antagonists,particularly to the P2Y2 receptor. Accordingly they are useful intherapy and are, in particular, indicated for use as anti-inflammatoryagents useful in a number of inflammatory diseases such as asthma,inflammatory bowel disease, ARDS, psoriasis, rheumatoid arthritis,myocardial ischaemia, COPD, cystic fibrosis, arthereosclerosis,restenosis, peridontal disease, septic shock, osteoarthritis and stroke.The compounds of the invention can be co-administered with otheranti-inflammatory agents. ATP receptors have also been reported ontumour cells and may be involved in the development of cancer.Antagonists may therefore be useful in treatment of cancer.

The invention provides in a further aspect a method of treating aninflammatory condition which comprise administering to a patient in needof therapy, a therapeutically effective amount of a compound of theinvention.

According to the invention there is further provided use of thecompounds of the invention in the manufacture of a medicament for use inthe treatment of an inflammatory condition.

The compounds may be administered orally, topically e.g. to the lungand/or the airways, in the form of solutions, suspensions, HFA areosolsand dry powder formulations, e.g. Turbuhaler® formulations or byparenteral administration in the form of sterile parenteral solutions orsuspensions.

The invention further provides a pharmaceutical composition comprising acompound according to the present invention in association with apharmaceutically acceptable excipient an/or adjuvant. Particularlypreferred are compositions not containing material capable of causing anadverse, e.g. an allergic, reaction. For example a chelating orsequestering agent, an antioxidant, a tonicity adjusting agent, a pHmodifying agent and/or a buffering agent are suitable additives.

The compound of the invention may also be administered by means of a drypowder inhaler. The inhaler may be a single or a multi dose inhaler, andmay be a breath actuated dry powder inhaler.

A pharmaceutical composition according to the present invention couldoptionally be prepared in freeze dried from using any lyophilisationtechniques commonly used within the pharmaceutical area. Upon use butbefore administration, such pharmaceutical compositions are generallyreconstituted in a pharmaceutically acceptable excipient. Preferably asolution of the pharmaceutical composition according to the inventionobtained after reconstitution is an isotonic solution. Such apharmaceutical composition according to the present invention whenreconstituted is preferably administered by injection, for exampleintravenously, subcutaneously or intramuscularly.

The invention is illustrated by the following examples which should notbe interpreted as limiting the invention. In the examples the NMRspectra were measured on a Varian Unity Inova 300 or 400 MHzspectrometer and the MS spectra measured as follows: EI spectra wereobtained on a VG 70-250S or Finnigan Mat Incos-XL spectrometer, ESI andAPCI spectra were obtained on Finnigan Mat SSQ7000 or a MicromassPlatform spectrometer. Where necessary, the reactions were performedunder an inert atmosphere of either nitrogen or argon. Where necessary,preparative HPLC separations were generally performed using a Novapak®,Bondapak®, or Hypersil® column packed with BDSC-18 reverse phase silicagel. Chromatography was generally performed using Matrex Silica 60®(35-70 micron)or Prolabo Silica gel 60® (35-75 micron) suitable forflash silica gel chromatography.

Example 13-[[5-[9H-Fluoren-9-yl]-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

i) 5-[9-Hydroxy-9H-fluoren-9-yl]-2′, 3′, 5′,-tris-O-[[1,1-dimethylethyl]dimethylsily]uridine

To a solution of 2′, 3′, 5′,-tris-O-[[1,1-dimethylethyl]dimethylsily]uridine (Synthesis, 1991, 4,283) (25 g) and N,N,N′,N′-tetramethylethylenediamine (12.5 ml) intetrahydrofuran (300 ml) at −78° C. was added sec-butyllithium (82 ml ofa 1.3 M solution in cyclohexane) over 10 minutes. After 45 minutes, asolution of 9-fluorenone (13 g) in tetrahydrofuran (40 ml) was added.The mixture was allowed to warm to room temperature and stirredovernight. The reaction was treated with saturated aqueous ammoniumchloride and extracted with dichloromethane. The combined extracts weredried (MgSO₄) and evaporated. Purification was by chromatography elutingwith 50% acetone in isohexane.

Yield 19.77 g.

MS: FAB(−ve): 765 (M−1)

ii) 5-[9H-Fluoren-9-yl]uridine

To a solution of the product of step (i) (10 g) and triethylsilane (2.3ml) in dichloromethane (50 ml) at 0° C. was added boron trifluoridediethyl etherate (3.2 ml). The mixture was stirred for 45 minutes thenevaporated to dryness and azeotroped with toluene. The residue wasdissolved in tetrahydrofuran (25 ml), treated with tetrabutyl ammoniumfluoride (16.8 g) and the mixture stirred overnight. The mixture wasevaporated and the residue purified by chromatography eluting with 10%methanol in dichloromethane. Yield 5 g.

MS:FAB(+ve): 409 (M+1)

iii) 5-[9H-Fluoren-9-yl]-3,4-dihydro-2,4(1H, 3H)-pyrimidinedione

A mixture of the product from step (ii) (0.67 g), ethanol (5 ml) and 6MHCl (20 ml) was heated at reflux for 84 hours. The mixture wasconcentrated under reduced pressure and water added. The resultantprecipitate was filtered off and dried. Yield 0.34 g.

1H NMR: δ (DMSO) 11.20(br s, 1H), 10.71(br s, 1H), 7.90(d,2H),7.50-7.20(d+t+t,6H), 6.90(br s,1H), 5.00(s,1H).

iv)3-[[5-[9H-Fluoren-9-yl]-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

To a stirred solution of the product from step (iii) (0.5 g) indimethylformamide (5 ml) at room temperature was addedtetraethylammonium hydroxide (1.31 ml). After 10 minutes methyl3-bromomethylbenzoate (0.435 g) was added and the mixture was stirredfor 20 minutes. The mixture was partitioned between ethyl acetate andwater. The organic phase was dried (MgSO₄) and evaporated. Purified bychromatography eluting with 20-40% ethyl acetate in isohexane. Yield0.23 g.

MS: EI(+ve): 424 (M⁺)

v)3-[[5-[9H-Fluoren-9-yl]-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

A mixture of the product from step (iv) (0.3 g) and Lawesson's reagent(0.286 g) in tetrahydrofuran (8 ml) was heated at reflux for 6 hoursthen cooled and partitioned between ethyl acetate and aqueous sodiumbicarbonate. The organic phase was dried (MgSO₄) and evaporated.Purified by chromatography eluting with 30-40% ethyl acetate inisohexane.

Yield 0.19 g

MS:FAB(+ve): 441 (M+1)

vi)3-[[5-[9H-Fluoren-9-yl]-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

A mixture of the product from step (v) (0.175 g) and lithium hydroxidemonohydrate (0.034 g) in tetrahydrofuran (3 ml) and water (3 ml) wasstirred at room temperature for 3 hours and partitioned betweendichloromethane and 2 M HCl. The organic phase was dried (MgSO₄) andevaporated under reduced pressure. Yield 0.095 g.

MS:FAB(+ve): 427 (M+1, 100%)

1H NMR: δ (DMSO) 13.16(s,1H), 13.05(br s, 1H), 8.00-7.22(m, 12H),7.04(s,1H), 5.99(s,1H), 4.84(s, 2H) plus rotamer.

MP: 261-263° C.

Example 23-[[5-[5H-Dibenzo[a,d]cyclohepten-5-yl]-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

i) 5-Bromo-2,4-bis(1,1-dimethylethoxy)pyrimidine

To a solution of potassium tert-butoxide (67.5 g) in tetrahydrofuran(500 ml) was added dropwise a solution of 5-bromo-2,4-dichloropyrimidine(55 g) (J.Am.Chem.Soc. 1934, 56, 134) in tetrahydrofuran (100 ml). After1.5 hours, water (100 ml) was added carefully and the mixture extractedwith ethyl acetate. The combined extract was washed with water, dried(MgSO₄) and evaporated under reduced pressure. Purification was bychromtography eluting with isohexane. Yield 52.4 g.

MS: GC-MS: 302/304 (M⁺⁾

ii) 5-(5H-Dibenzo[a,d]cyclohepten-5-yl)-2,4(1H,3H)-pyrimidinedione

To a solution of the product of step (i) (50 g) in dry tetrahydrofuran(11) at −78° C. was added n-butyllithium (69 ml of a 2.5 M solution inhexanes) dropwise. After 0.5 hours a solution of5H-dibenzo[a,d]cyclohepten-5-one (44 g) in tetrahydrofuran (100 ml) wasadded. The reaction mixture was stirred at −78° C. for three hours andthen allowed to warm to room temperature overnight. Saturated aqueousammonium chloride solution (400 ml) was added and the mixture extractedwith ethyl acetate. The organic solution was dried (MgSO₄) andevaporated under reduced pressure to give the crude5-[2,4-bis[1,1-dimethylethoxy]pyrimidin-5-yl]-5H-dibenzo[a,d]cyclohepten-5-olwhich was used directly.

To stirred solution of this product and triethylsilane (64 ml) in drydichloromethane (400 ml) at 0° C. was added trifluoroacetic acid (150ml) dropwise over ten minutes. The cooling bath was removed and thesolution was stirred at room temperature overnight. Toluene (300 ml) wasadded and solution was evaporated under vacuum. The residue wasazeotroped with toluene (3 times). The oil was treated with diethylether and the precipitated product collected as a white powder. Yield 44g.

MS: EI: 302 (M+, 100%)

iii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

To a solution of the product from step (ii) (0.7 g) in DMSO (5 ml) wasadded cesium carbonate (0.75 g). After 5 minutes a solution of3-bromomethylbenzoic acid methyl ester (0.53 g) in DMSO (5 ml) wasadded. The mixture was stirred at room temperature for 20 minutes andpartitioned between ethyl acetate and water. The organic phase waswashed with water and brine, dried (MgSO₄) and evaporated. Purified bychromatography eluting with 30% ethyl acetate in isohexane. Yield 0.34g.

MS: FAB(+ve): 451 (M+1)

iv)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (iii) (0.34g) by the method of example 1 step (v). Yield 0.22 g.

MS: FAB(+ve): 467 (M+1)

v)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

The title compound was prepared from the product of step (iv) (0.22 g)by the method of example 1 step (vi). Yield 0.04 g.

MS: FAB(+ve): 453 (M+1)

1H NMR: δ (DMSO) 13.16(br s,1H), 12.65(s,1H), 7.96(d,1H), 7.85(s,1H),7.60-7.50(m,4H), 7.36-7.23(m,6H), 6.99(s,1H), 6.73(s,2H), 5.80(s,1H),4.89(s,2H).

MP:>230° C.

Example 33-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4thioxo-1(2H)-pyrimidinyl]methyl]benzeneacetic acid

i) 3-[Bromomethyl]benzeneacetic acid, ethyl ester

A mixture of [3-methylphenyl]acetic acid ethyl ester (5g),N-bromosuccinimide (5 g) and benzoyl peroxide (0.1 g) in dichloromethane(200 ml) was irradiated under a 500 W halogen lamp for 6 hours. Thesolvent was evaporated and the residue partitioned between diethyl etherand water. The organic phase was dried (MgSO₄) and evaporated. Purifiedby chromatography eluting with 5-10% ethyl acetate in isohexane. Yield5.14 g.

MS: GC-MS: 256/258 (M⁺⁾

ii)3[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzeneaceticacid, ethyl ester

The subtitle compound was prepared from the product of step (i) (0.85 g)and example 2 step (ii) (1.0 g) by the method of example 2 step (iii).Purification was by chromatography eluting with 50% ethyl acetate inisohexane. Yield 0.74 g.

MS: FAB(+ve): 479 (M+1, 100%)

iii)3-[[5{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzeneaceticacid, ethyl ester

The subtitle compound was prepared from the product of step (ii) (0.6 g)by the method of example 1 step (v). Purification was by chromatographyeluting with 20% ethyl acetate in isohexane. Yield 0.37 g.

MS: APCI(+ve): 495 (M+1, 100%)

iv)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzeneaceticacid

The title compound was prepared from the product of step (iii) (0.36 g)by the method of example 1 step (vi). Yield 0.19 g.

MS: APCI(+ve): 467 (M+1, 100%)

1H NMR: δ (DMSO) 12.62(s,1H), 12.45(br s,1H), 7.58-7.08(m, 12H),6.89(s,1H), 6.62(s,2H), 5.79(s,1H), 4.78(s,2H), 3.63(s,2H).

MP: 135-137° C.

Example 43[[5-{5H-Dibenzo[a,d]cyclohepten-5yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzenephosphonicacid

i) 3-Methylbenzenephosphonic acid, diethyl ester

To a solution of 3-bromotoluene (5 g) in tetrahydrofuran at −78° C. wasadded tert-butyllithium (35 ml of a 1.7 M solution in pentane). Themixture was stirred at −78° C. for 1 hour and diethl chlorophosphate(5.1 ml) was added. After 2 hours the mixture was warmed to 0° C.,quenched with aqueous ammonium chloride and partitioned between ethylacetate and water. The organic phase was dried (MgSO₄) and evaporated.Purified by chromatography eluting with 40% ethyl acetate in isohexane.Yield 2.7 g.

MS: GC-MS: 228 (M⁺)

ii) 3-[Bromomethyl]benzenephosphonic acid, diethyl ester

The subtitle compound was prepared from the product of step (i) (2.64 g)by the method of example 3 step (i). Purification was by chromatographyeluting with 40% ethyl acetate in isohexane. Yield 1.42 g.

MS: GC-MS: 306/8 (M⁺)

iii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzenephosphonicacid, diethyl ester

The subtitle compound was prepared from the product of step (ii) (1.27g) by the method of example 2 step (iii). Yield 0.5 g.

MS: FAB(+ve): 529 (M+1, 100%)

iv)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzenephosphonicacid, diethyl ester

To a stirred solution of the product from step (iii) (0.5 g) indimethylformamide (10 ml) at 0° C. was added trimethylsilyl bromide(0.265 ml). After 1 hour the mixture was stirred at room temperature andthen treated with a further 0.265 ml trimethylsilyl bromide. Two furtheraliquots were added after 2 and 4 hours. The mixture was evaporated andthe residue dissolved in methanol (10 ml) and stirred overnight. Thesolution was concentrated under reduced pressure to 5 ml and treatedwith sodium bicarbonate (0.21 g) and water (5 ml). The mixture wasstirred for 10 minutes and purified by reverse phase chromatography. Theproduct was obtained by lyophilisation. Yield 0.085 g.

MS: APCI(+ve): 472 (M−2Na+2)

1H NMR: δ (D₂O) 7.59-7.15(m,11H), 6.76(d,1H), 6.59(s, 2H), 6.37(s,1H),5.13(s,1H), 4.37(s,1H).

MP: 348° C.

Example 55-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-methoxybenzoicacid

i) 5-Bromomethyl-2-methoxybenzoic acid, methyl ester

A mixture of 2-methoxy-5-methylbenzoic acid methyl ester(J.Chem.Soc.Perkin Trans.1, 1994, 1125) (1.47 g) and N-bromosuccinimide(1.45 g) in benzene (15 ml) was irradiated under a 500 W halogen lampfor 3 hours. The solvent was evaporated and the residue triturated withdiethyl ether. The succinimide was filtered off and the filtrateevaporated.

The residue was triturated with isohexane and the product collected byfiltration. Yield 1.41 g. Used directly in the next step.

ii)5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-2-methoxybenzoicacid, methyl ester

The subtitle compound was prepared from the product of step (i)(0.9 g)and example 2 step (ii) (1.05 g) by the method of example 2 step (iii).Purification was by chromatography eluting with 30% ethyl acetate inisohexane. Yield 0.36 g.

1H NMR: δ (DMSO) 11.20(s,1H), 7.55(d,4H), 7.40-7.25(m,8H), 7.20(d,1H),6.70(s,2H), 6.60(s,1H), 5.30(s,1H), 4.70(s,2H), 3.86(s,6H).

iii)5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-methoxybenzoicacid, methyl ester

A mixture of the product from step (ii) (0.36 g) and phosphorouspentasulphide (0.66 g) in dry pyridine (10 ml) was heated at 115° C. for16 hours. The mixture was partitioned between ethyl acetate and water.The organic phase was washed with brine, dried (MgSO₄) and evaporated.Purified by chromatography eluting with 40% ethyl acetate in isohexane.Yield 0.16 g.

MS: FAB(+ve): 497 (M+1)

iv)5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-methoxybenzoicacid.

The title compound was prepared from the product of step (iii) (0.126 g)by the method of example 1 step 9 vi).

Yield 0.063 g.

MS: APCI(+ve): 483 (M+1, 100%)

1H NMR: δ (DMSO) 12.83(br,s,1H), 12.60(s,1H), 7.57(m,3H),7.40-7.20(m,7H), 7.18(d,1H), 6.94(s,1H), 6.73(s,2H), 5.79(s,1H),4.76(s,2H), 3.87(s,3H).

Example 62-[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5yl}-3,4-dihydro-2oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]-4-thiazolecarboxylicacid

i) 2-[3-Methylphenyl]-4-thiazolecarboxylic acid, ethyl ester

Hydrogen sulphide gas was bubbled into a solution of m-toluonitrile (10g) in triethylamine (30 ml) and pyridine (20 ml) for 3 hours. Thesolvents were evaporated and the residue azeotroped with toluene thenpassed through a plug of silica gel eluting with 10% ethyl acetate indichloromethane. A mixture of the product (9.05 g) and ethylbromopyruvate (9 ml) in ethanol (175 ml) was heated at reflux overnight.The mixture was evaporated and the reside partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organic phase wasdried (MgSO₄) and evaporated. Purified by chromatography eluting with20% ethyl acetate in isohexane. Yield 7.91 g. Used directly in the nextstep.

ii) 2-[3-[Bromomethyl]phenyl]-4-thiazolecarboxylic acid, ethyl ester

The subtitle compound was prepared from the product from step (i) (3 g)by the method of example 5 step (i). Yield 2.2 g, Used directly in thenext step.

iii)2-[3-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1-(2H)-pyrimidinyl]methyl]-phenyl]-4-thiazolecarboxylicacid, methyl ester

The subtitle compound was prepared from the product of step (ii) (0.87g) by the method of example 2 step (iii). Purification was bychromatography eluting with 30% ethyl acetate in isohexane. Yield 1.0 g.Used directly in the next step.

iv)2-[3-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-phenyl]-4-thiazolecarboxylicacid, ethyl ester

The subtitle compound was prepared from the product of step (iii) (1.1g) by the method of example 1 step (v) using 1,4-dioxane as solvent.Yield 0.5 g.

MS: ESI(+ve): 564 (M+1, 100%)

v)2-[[3-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]-4-thiazolecarboxylicacid

The title compound was prepared from the product of step (iv) (0.3 g) bythe method of example 1 step (vi). Yield 0.22 g.

MS: APCI(+ve): 536 (M+1, 100%)

1H NMR: δ (DMSO) 13.26(br,s,1H), 12.64(br,s1H), 8.59(s,1H), 8.00(d,1H),7.98(s,1H), 7.60-7.20(m,10H), 7.00(s,1H), 6.78(s,2H), 5.79(s,1H),4.91(s,2H).

MP: 165° C.

Example 73-[[5-{5H-Dibenzo[a,d]cyclohepten-5yl}-3,4-dihydro-2oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[2-methoxyethoxymethyl]benzoicacid

i) 3-Bromomethyl-5-[2-methoxyethoxymethyl]benzoic acid ethyl ester

Sodium hydride (0.357 g, 60% dispersion in oil) was added to2methoxyethanol (10 ml) with stirring. After 10 minutes3,5-bis[bromomethyl]benzoic acid ethyl ester (J. Chem. Soc. Chem.Commun. 1992, 22, 1647) (3 g) was added and the mixture stirred for 3hours. The mixture was partitioned between ethyl acetate and water. Theorganic phase was dried (MgSO₄) and evaporated. Purified bychromatography eluting with 20% ethyl acetate in isohexane. Yield 0.45g.

MS: GC-MS: 330/2 (M⁺)

ii)3-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-5-[2-methoxyethoxymethyl]benzoicacid, ethyl ester

A mixture of example 2 step (ii) (0.41 g) andbis[trimethylsilyl]trifluoroacetamide (0.73 g) in 1,2-dichloroethane (10ml) was heated at reflux for 1 hour. The product from step (i) (0.45 g)was added and the mixture was heated at reflux for 7 hours. The mixturewas evaporated and the residue purified by chromatography eluting with30% ethyl acetate in isohexane. Yield 0.52 g.

MS: APCI(+ve): 553 (M+1)

iii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[2-methoxyethoxymethyl]benzoicacid, ethyl ester

The subtitle compound was prepared from the product of step (ii) (0.52g) by the method of example 6 step (iv). Purification was bychromatography eluting with 30-20% ethyl acetate in toluene. Yield 0.457g.

MS: APCI(+ve): 569 (M+1, 100%)

iv)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[2-methoxyethoxymethyl]benzoicacid

The title compound was prepared from the product of step (iii) (0.457 g)by the method of example 1 step (vi). Yield 0.216 g.

MS: APCI(+ve): 541 (M+1, 100%)

1H NMR: δ (DMSO) 12.64(s,1H), 7.92(s,1H), 7.76(s,1H), 7.58(d,2H),7.45(s,1H), 7.37-7.23(m,6H), 6.97(s,1H), 6.72(s,2H), 5.80(s,1H),4.88(s,2H), 4.59(s,2H), 3.67(m,2H), 3.52(m,2H), 3.27(s,3H).

MP: 194-195° C.

Example 83-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[phenoxymethyl]benzoicacid

i) 3-Bromomethyl-5-[phenoxymethyl]benzoic acid ethyl ester

The subtitle compound was prepared from 3,5-bis[bromomethyl]benzoic acidethyl ester (5.18 g) and phenol (1.45 g) in dimethylformamide (10 ml) bythe method of example 7 step (i). Yield after chromatography, elutingwith 10% ethyl acetate in isohexane, 2.13 g of a mixture containing 15%product and 85% diphenoxy compound.

MS: GC-MS: 248/9 (15%)

ii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-5-[phenoxymethyl]benzoicacid, ethyl ester

The subtitle compound was prepared from the product of step (i) (1.29mmol) and example 2 step (iv) (0.39 g) by the method of example 7 step(ii). Purification was by chromatography eluting with 30% ethyl acetatein isohexane. Yield 0.564 g.

MS: APCI(+ve): 561 (M+1 %)

iii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[phenoxymethyl]benzoicacid, ethyl ester

The subtitle compound was prepared from the product of step (ii)(0.564g) by the method of example 6 step (iv). Purification was bychromatography eluting with 25% ethyl acetate in toluene. Yield 0.44 g.

MS: APCI(+ve): 587 (M+1, 100%)

iv)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[phenoxymethyl]benzoicacid

The title compound was prepared from the product of step (iii) (0.44 g)by the method of example 1 step (vi). Purified by reverse phase HPLC.Yield 0.037 g.

MS: APCI(+ve): 559 (M+1)

1H NMR δ (DMSO) 8.05(s,1H), 7.81(s, 1H), 7.60-7.57(m,3H),7.38-7.21(m,8H), 7.08-7.04(m,2H), 7.00-6.95(m,2H),6.72(s,2H),5.80(s,1H),5.21(s,2H),4.91(s,2H).

MP: 160-165° C.

Example 93-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,5-dihydro-2-oxo-4thioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxymethyl]benzoicacid

i) 3-Bromomethyl-5-{ethoxymethyl}benzoic acid, ethyl ester

A stirred solution of 3,5-bis[bromomethyl]benzoic acid ethyl ester (3g)in ethanol (100 ml) was treated with potassium ethoxide (0.75 g) andstirred overnight. The mixture was partitioned between ethyl acetate andwater. The organic phase was dried (MgSO₄) and evaporated and theresidue purified by chromatography eluting with 10% ethyl acetate inisohexane. Yield 1.3 g.

MS: GC-MS: 300/302 (M⁺)

ii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxymethyl]benzoicacid, ethyl ester

The subtitle compound was prepared from the product of step (i) (1.3 g)and example 2 step (ii) (1.31 g) by the method of example 7 step (ii),Yield 1.28 g.

MS:ESI(+ve): 523 (M+1, 100%)

iii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4dihydro-2-oxo4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxymethyl]benzoicacid, ethyl ester

the subtitle compound was prepared from the product of step (ii) (1.28g) by the method of example 6 step (iv). Yield 0.86 g.

MS: APCI(+ve): 539 (M+1)

iv)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxymethyl]benzoicacid

The title compound was prepared from the product of step (iii) (0.85 g)by the method of example 1 step (vi). Purified by reverse phase HPLC.Yield 0.113 g.

MS: APCI(+ve); 51 (M+1, 100%)

1H NMR δ (DMSO) 12.64(s,1H), 7.91(s, 1H), 7.76(s,1H), 7.58(d,2H),7.44(s,1H), 7.37-7.22(m,6H), 6.98(s,1H), 6.72(s,2H), 5.80(s,1H),4.88(s,2H), 4.55(s,2H), 3.55(q,2H), 1.20(t,3H).

MP:>240° C.

Example 101-[[3-[[3Carboxy-5-{5H-dibenzo[a,d]cyclohepten-5yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-4pyrazolecarboxylicacid, ethyl ester

A solution of ethyl 4-pyrazolecarboxylic (0.5 g) in dimethylformamide (3ml) was added dropwise to a suspension of sodium hydride (0.143 g) indimethylformamide (7 ml). The mixture was stirred for 1.5 hours andtransferred into a solution of 3,5bis[bromomethyl]benzoic acid ethylester in dimethylformamide (30 ml). The mixture was stirred at roomtemperature for 2 hours and partitioned between ethyl acetate and water.The organic phase was dried (MgSO₄), evaporated and purified bychromatography eluting with 20% ethyl acetate in isohexane. Yield 0.8 g.

1H NMR δ (CDCl₃) 8.04(s,1H), 7.96(s, 1H), 7.92(s,1H), 7.87(s,1H),7.45(s,1H), 5.35(s,2H), 4.48(s,2H), 4.36(q,2H), 4.28(q,2H), 1.41(t,3H),1.34(t,3H).

ii)1-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxycarbonyl]phenyl]methyl]-4-pyrazolecarboxylicacid, ethyl ester

The subtitle compound was prepared from the product of step (i) (0.79 g)and example 2 step (ii) (1.2 g) by the method of example 2 step (iii).Yield 0.72 g.

MS: APCI(+ve): 617(M+1, 100%)

iii)1-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxycarbonyl]phenyl]methyl]-4-pyrazolecarboxylicacid, ethyl ester

The subtitle compound was prepared from the product of step (ii) (0.71g) by the method of example 6 step (iv). Yield 0.33 g.

MS: APCI(+ve): 633 (M+1, 100%)

iv)1-[[3-[[3-Carboxy-5-{5H-dibenzo[a,d]cyclohepten-5-yl}3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-4-pyrazolecarboxylicacid

The title compound was prepared from the product of step (iii) (0.32 g)by the method of example 1 step (vi). Purified by reverse phase HPLC.Yield 0.03 g.

MS: APCI(+ve): 577 (M+1, 100%)

1H NMR δ (DMSO) 12.64(s,1H), 8.50(s, 1H), 7.90(s,1H), 7.87(s,1H),7.76(s,1H), 7.59-7.22(m,9H), 6.91(s,1H), 6.61(s,2H), 5.78(s,1H),5.49(s,2H), 4.87(s,2H).

MP: 210-212° C.

Example 113-[[3-[[3Carboxy-5-{5H-Dibenzo[a,d]cyclohepten-5yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methoxy]-5ethoxybenzoicacid

i) 3 Ethoxy-5-hydroxybenzoic acid, methyl ester

Sodium hydride (1.19 g) was added to an ice-cold solution of methyl3,5-dihydroxybenzoate (5 g) in dimethylformamide. The mixture wasstirred at room temperature for 1 hour. Ethyl iodide (2.67 ml) was addedand the mixture was stirred for 16 hours. The mixture was evaporated andthe residue partitioned between ethyl acetate and by chromatographyeluting with 25% ethyl acetate in isohexane. Yield 2.03 g.

MS: GC-MS: 196 (M⁺)

ii) 3-[[3-Bromomethyl-5-[ethoxycarbonyl]phenyl]methoxy]-5-ethoxybenzoicacid, methyl ester

Sodium hydride (0.45 g) was added to a solution of the product from step(i) (2 g) in dimethylformamide (30 ml) with ice-cooling,3,5-Bis[bromomethyl]benzoic acid ethyl ester (3.42 g) was added and themixture was stirred for 16 hours. The solvent was evaporated and theresidue partitioned between ethyl acetate and water. The organic phasewas washed with water, dried (MgSO₄) and evaporated, Purified bychromatography eluting with 25% ethyl acetate in isohexane. Yield 1.21 gof a mixture (60% product, 40% dimer by ¹H NMR). Used directly in thenext step.

iii)3-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1-(2H)-pyrimidinyl]methyl]-5-[ethoxycarbonyl]phenyl]methoxy]-5-ethoxybenzoicacid, methyl ester

The subtitle compound was prepared from the product of step (ii) (1.64mmol) and example 2 step (ii) (0.49 g) by the method of example 7 step(ii). Purification was by chromatography eluting with 505 ethyl acetatein isohexane. Yield 0.7 g.

MS: APCI(+ve): 673 (M+1, 100%)

iv)3-[[3-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxycarbonyl]phenyl]methoxy]-5-ethoxybenzoicacid, methyl ester

The subtitle compound was prepared from the product of step (iii) (0.7g) by the method of example 6 step (iv). Purification was bychromatography eluting with 25% ethyl acetate in isohexane. Yield 0.6 g.

MS: APCI(+ve): 689 (M+1, 100%)

v)3-[[3-Carboxy-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methoxy]-5-ethoxybenzoicacid

The title compound was prepared from the product of step (iv) (0.6 g) bythe method of example 1 step (vi). Yield 0.1 g.

MS: APCI(+ve): 647 (M+1, 100%)

1H NMR δ (DMSO) 8.05(s,1H), 7.81(s, 1H), 7.58(m,3H), 7.40-7.20(m,8H),7.09(s,1H), 6.99(s,1H), 6.85(s,1H), 6.71(s,2H), 5.79(s,1H), 5.25(s,2H),4.90(s,2H), 4.07(q,2H), 1.33(t,3H).

MP: 180-183° C.

Example 123-[[3-Carboxy-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methoxy]-5-[2-methoxyethoxy]benzoicacid

i) 3-Hydroxy-5-[phenylmethoxy]benzoic acid, methyl ester

The subtitle compound was prepared from methyl 3,5-dihydroxybenzoate (5g) and benzyl bromide (3.6 ml) by the method of example 11 step (i).Purification was by chromatography eluting with 30% ethyl acetate inisohexane. Yield 2.31 g.

MS: GC-MS: 258 (M⁺)

ii) 3-[2-Methoxyethoxy]-5-[phenylmethoxy]benzoic acid, methyl ester

The subtitle compound was prepared from the product of step (i) (2.31 g)and 2-bromoethyl methyl ether 90.92 ml) by the method of example 11 step(i). Yield 2.74 g.

MS: GC-MS: 316 (M⁺)

iii) 3-Hydroxy-5-[2-methoxyethoxy]benzoic acid, methyl ester

The product from step (ii) (2.74 g) was reduced by catalytichydrogenation at 1 at. for 16 hours in ethyl acetate solution with 10%palladium on charcoal. Yield 1.5 g.

MS: GC-MS: 226 (M⁺)

iv)3-[[3-Bromomethyl-5-[ethoxycarbonyl]phenyl]methoxy]-5-[2-methoxyethoxy]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (iii) (1.5g) and 3,5-bis(bromomethyl)benzoic acid ethyl ester (4.9g) by the methodof example 11 step (i). Purification was by chromatography eluting with30% ethyl acetate in isohexane. Yield 1.6 g. Used directly in the nextstep

v)3-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4dihydro-2,4-oxo-4-dioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxycarbonyl]phenyl]methoxy]-5-[2-methoxyethoxy]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (iv) (1.6 g)and example 2 step (ii) (1 g) by the method of example 7 step (ii).Purification was by chromatography eluting with 50% ethyl acetate inisohexane. Yield 1.47 g.

MS: APCI(+ve): 703 (M+1, 100%)

vi)3-[[3-[[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxycarbonyl]phenyl]methoxy]-5-[2-methoxyethoxy]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (v) (1.5 g)by the method of example 6 step (iv). Purification was by chromatographyeluting with 50% ethyl acetate in isohexane. Yield 0.37 g.

MS: APCI(+ve) 719 (M+1, 100%)

vii)3-[[3-Carboxy-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methoxy]-5-[2-methoxyethoxy]benzoicacid

The title compound was prepared from the product of step (vi) (0.37 g)by the method of example 1 step (vi). Yield 0.23 g.

MS: APCI(+ve): 677(M+1, 100%)

1H NMR δ (DMSO) 8.03(s,1H), 7.79(s, 1H), 7.57(d,2H), 7.46(s,1H),7.40-7.10(m,12H), 6.98(s,1H), 6.80(s,1H), 6.72(s,2H), 5.79(s,1H),5.20(s,2H), 4.87(s,2H), 4.12(br s,2H), 3.65(br s,2H), 3.30(s,3H).

Example 133-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4thioxo-1(2H)-pyrimidinyl]methyl]-5-[hydroxymethyl]benzoicacid

i) 3-Acetoxymethyl-5-[bromomethyl]benzoic acid, ethyl ester

To a stirred solution of 18-crown-6 (0.103 g) in acetonitrile (15 ml)was added potassium acetate (0.38 g). After 30 minutes3,5-bis[bromomethyl]benzoic acid ethyl ester (2.61 g) was added and themixture was stirred overnight. The mixture was partitioned between ethylacetate and water. The organic phase was dried (MgSO₄) and evaporatedand the residue purified by chromatography eluting with 10% ethylacetate in isohexane. Yield 0.97 g.

MS: GC-MS: 314/316 (M⁺)

ii) 3-[Acetoxymethyl]-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzoic acid,ethyl ester

The subtitle compound was prepared from the product of step (i) (0.92 g)and example 2 step (ii) (0.88g) by the method of example 2 step (iii).Purification was by chromatography eluting with 40% ethyl acetate intoluene. Yield 0.92 G.

1H NMR δ (DMSO) 11.25(s,1H), 7.95(s, 1H), 7.75(s,1H), 7.53(d,2H),7.48(s,1H), 7.38-7.33(m,2H), 7.31-7.23(m,5H), 6.71(s,2H), 6.67(s,1H),5.32(s,1H), 5.18(s,2H), 4.84(s,2H), 4.39(q,2H), 2.11(s,3H), 1.37(t,3H).

Example 143-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4thioxo-1(2H)-pyrimidinyl]methyl]-5-methylbenzoicacid

i) 3-Bromomethyl-5-methylbenzoic acid, ethyl ester

The subtitle compound was prepared from ethyl 3,5-dimethylbenzoate (2 g)and N-bromosuccinimide (2 g) by the method of example 5 step (i).Purification was by chromatography eluting with 5% ethyl acetate inisohexane Yield 1.85 g.

1H NMR δ (CDCl₃), 7.86(s,1H), 7.79(s,1H), 7.40(s,1H), 4.49(s,2H),4.37(q,2H), 2.40(s,3H), 1.40(t,3H).

ii)3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-dioxo-1(2H)-pyrimidinyl]methyl]-5-methylbenzoicacid, ethyl ester

The subtitle compound was prepared from the product of step (i) (0.85 g)and example 2 step (ii) (1 g) by the method of example 2 step (iii).Purification was by chromatography eluting with 25% ethyl acetate inisohexane. Yield 0.85 g.

1H NMR δ (CDCl₃) 8.55(s,1H), 7.88(s, 1H), 7.65(s,1H), 7.51(s,1H),7.49(s,1H), 7.38-7.33(td,2H), 7.27-7.16(m,4H), 6.57(s,2H), 6.54(s,1H),5.32(s,1H), 4.69(s,2H), 4.48-4.42(q,2H), 2.42(s,3H), 1.48-1.44(t,3H).

iii)3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-methylbenzoicacid, ethyl ester

The subtitle compound was prepared from the product of step (ii) (0.85g) by the method of example 5 step (iii). Purification was bychromatography eluting with 20% ethyl acetate in toluene. Yield 0.41 g.

1H NMR δ (DMSO) 12.63(s,1H), 7.81(s, 1H), 7.67(s,1H), 7.58(d,2H),7.36-7.23(m,7H), 6.94(s,1H), 6.78(s,2H), 5.80(s,2H), 4.84(s,2H),4.38(q,2H), 2.41(s,3H), 1.37(t,3H).

iv)3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-methylbenzoicacid

The title compound was prepared from the product of step (iii) (0.412 g)by the method of example 1 step (vi). Purified by reverse phase HPLC.Yield 0.128 g.

MS: APCI(+ve): 467 (M+1, 100%)

1H NMR δ (DMSO) 7.78(s,1H), 7.65(s, 1H), 7.59-7.57(d,2H),7.36-7.20(m,7H), 6.96(s,1H), 6.72(s,2H), 5.80(s,1H), 4.81(s,2H),2.38(s,3H). 6.94(s,1H), 6.78(s,2H), 5.80(s,2H), 4.84(s,2H), 4.38(q,2H),2.41(s,3H), 1.37(t,3H).

MP:>240° C.

Example 155-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4thioxo-1(2H)-pyrimidinyl]methyl]-2-hydroxybenzoicacid

i) 2-Hydroxy-5-methylbenzoic acid, methyl ester

To a solution of 5-methylsalicylic acid (7.24 g) in methanol (250 ml)was added trimethylsilyl chloride (60 ml). The mixture was heated atreflux for 2 hours and stirred at room temperature overnight. A further60 ml trimethylsilyl chloride was added and the mixture heated at refluxfor 6 hours. The mixture was evaporated and the residue partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic phase was dried (MgSO₄) and evaporated to give the crudeproduct. Yield 5.87 g. Used directly in the next step.

ii) 2Acetoxy-5-methylbenzoic acid, methyl ester

A solution of the product from step (i) (5.87 g) in acetic anhydride(4.32 g) was treated with concentrated sulphuric acid (0.5 ml) andstirred for 72 hours. The mixture was poured into ice-water andextracted with diethyl ether. The extract was washed with water andsaturated aqueous sodium bicarbonate, dried (MgSO₄) and evaporated.Yield 5.5 g.

1 H NMR: δ (CDCl₃), 8.04(d,1H), 7.58(dd,1H), 7.09(d, 1H), 4.49(s,2H),3.88(s,3H), 2.35(s,3H).

iii) 2-Acetoxy-5-[bromomethyl]benzoic acid, methyl ester The subtitlecompound was prepared from the product of step (ii) (2 g) by the methodof example 5 step (i). Purification was by chromatography eluting with5% ethyl acetate in isohexane. Yield 1.7 g.

1H NMR: δ (CDCl₃) 8.04(d,1H), 7.58(dd,1H), 7.09(d,1H), 4.49(s,2H),3.88(s,3H), 2.35(s,3H).

iv)2-Acetoxy-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (iii) (1.66g) and example 2 step (ii) (1.75 g) by the method of example 2 step(iii). Purification was by chromatography eluting with 30% ethyl acetatein isohexane. Yield 1.05 g.

1H NMR δ (DMSO) 11.27(s,1H), 7.77(d,1H), 7.77-7.48(m,3H),7.38-7.23(m,5H), 7.18-7.12(m,2H), 6.77(s,2H), 6.63(s,1H), 5.31(s,1H),4.82(s,2H), 3.88(s,3H), 2.33(s,3H).

v)2-Acetoxy-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (iv) (1.05g) by the method of example 6 step (iv). Purification was bychromatography eluting with 10-20% ethyl acetate in toluene. Yield 0.74g.

MS: APCI(+ve): 525 (M+1, 100%)

vi)5-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4thioxo-1(2H)-pyrimidinyl]methyl]-2-hydroxybenzoicacid

The title compound was prepared from the product of step (v) (0.64 g) bythe method of example 1 step (vi). Purified by reverse phase HPLC. Yield0.121 g.

MS: ESI-: 467 (M+1, 100%)

1H NMR δ (DMSO) 11.50(br s,1H), 7.62(d,1H), 7.55(d,2H), 7.29-7.25(m,6H),7.00(dd,1H), 6.92(s,1H), 6.73(s,2H), 6.73-6.65(d,1H), 5.81(s,1H),4.62(s,2H).

MP:>240° C.

Example 16[3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4thioxo-1(2H)-pyrimidinyl]methyl]phenoxy]aceticacid

i) [3-Methylphenoxy]acetic acid, methyl ester

A mixture of m-cresol (10.8 g), methyl bromoacetate (15.3 g) andpotassium carbonate (69 g) in dimethylformamide (200 ml) was stirredovernight and partitioned between ethyl acetate and water. The organicphase was washed with water, dried (MgSO₄) and evaporated. Purified bychromatography eluting with toluene. Yield 12.7 g.

1H NMR δ (CDCl₃) 7.17(t,1H), 6.82(d,1H), 6.74(s,1H), 6.70(dd,1H),4.62(s,2H), 3.80(s,3H), 2.33(s,3H).

ii) [3-[Bromomethyl]phenoxy]acetic acid, methyl ester

The subtitle compound was prepared from the product of step (i) (12.7 g)by the method of example 5 step (i). Purified by chromatography elutingwith 5% ethyl acetate in isohexane. Yield 11.4 g.

1H NMR δ (CDCl₃) 7.27(t,1H), 6.94(s,1H), 6.84(d,1H), 4.65(s,2H),4.45(s,2H), 3.82(s,3H).

iii)[3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]phenoxy]aceticacid, methyl ester

The subtitle compound was prepared from the product of step (ii) (1.28g) and example 2 step (ii) (1.5 g) by the method of example 2 step(iii). Purification was by chromatography eluting with 30% ethyl acetatein isohexane. Yield 1.0 g.

1H NMR δ (DMSO) 11.23(s,1H), 7.52(d,2H), 7.37-7.23(m,7H), 6.92(dd,1H),6.76-6.71(m,4H), 6.58(s,1H), 5.30(s,1H), 4.81(s,2H), 4.71(s,2H),3.72(s,3H).

iv)[3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenoxy]aceticacid, methyl ester

The subtitle compound was prepared from the product of step (iii) (1 g)by the method of example 6 step (iv). Purification was by chromatographyeluting with 10-20% ethyl acetate in toluene. Yield 0.75 g.

MS: APCI(+ve): 497 (M+1, 100%)

v)[3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenoxy]aceticacid

The title compound was prepared from the product of step (iv) (0.61 g)by the method of example 1 step (vi). Purified by reverse phase HPLC.Yield 0.4 g.

MS: ESI(+ve): 483 (M+1, 100%)

1H NMR δ (DMSO) 7.57(d,2H), 7.35-7.22(m,7H), 6.89(m,2H), 6.76(s,1H),6.71(d,1H), 6.67(s,2H), 5.80(s,1H), 4.72(s,2H), 4.43(s,2H).

MP: 148-155° C.

Example 172Bromo-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

i) 2-Bromo-5-methylbenzoic acid, methyl ester

A solution of 2-bromo-5-methylbenzoic acid (10 g) in trimethylsilylchloride (30 ml) and methanol (100 ml) was stirred at room temperatureovernight and evaporated. The residue was partitioned between ethylacetate and sodium bicarbonate solution, dried (MgSO₄) and evaporated.Yield 10.1 g.

1H NMR δ (CDCl₃) 7.60(d,1H), 7.52(d,1H), 7.13(dd,1H), 3.92(s,3H),2.33(s,3H).

ii) 2-Bromo-5-[bromomethyl]benzoic acid, methyl ester

The subtitle compound was prepared from the product of step (i) (1.75 g)by the method of example 5 step (i). Purified by chromatography elutingwith 15% ethyl acetate in isohexane. Yield 1.9 g.

1H NMR δ (CDCl₃) 7.82(d,1H), 7.64(d,1H), 7.36(dd,1H), 4.44(s,2H),3.94(s,3H).

iii)2-Bromo-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (ii) (1.85g) and example 2 step (ii) (1.8 g) by the method of example 2 step(iii). Purification was by chromatography eluting with 30% ethyl acetatein toluene. Yield 1 g.

1H NMR δ (DMSO) 11.26(s,2H), 7.80(d,1H), 7.58(s,1H), 7.53(d,2H),7.40-7.20(m,7H), 6.73(s,2H), 6.63(s,1H), 5.30(s,1H), 4.78(s,2H),3.93(s,3H).

iv)2-Bromo-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

the subtitle compound was prepared from the product of step (iii) (1 g)by the method of example 5 step (iii). Purification was bychromatography eluting with 25% ethyl acetate in toluene. Yield 0.4 g.

1H NMR δ (DMSO) 12.65(s,1H), 7.82(d,1H), 7.66(s,1H), 7.58(d,2H),7.40-7.10(m,7H), 6.90(s,1H), 6.72(s,2H), 5.79(s,1H), 4.84(s,2H),3.93(s,3H).

v)2-Bromo-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

The title compound was prepared from the product of step (iv) (0.35 g)by the method of example 1 step (vi). Purified by reverse phase HPLC.Yield 0.22 g.

MS: APCI (+ve): 531/533

1H NMR δ (DMSO) 7.56(d,2H), 7.51(d,1H), 7.40-7.20(m,7H), 6.97(d,1H),6.88(s,1H), 6.80(s,2H), 5.77(s,1H), 4.74(s,2H).

MP: 170-185° C.

Example 185-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4thioxo-1(2H)-pyrimidinyl]methyl]-2-[phenylmethyl]benzoicacid

i)5-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-2-[phenylmethyl]benzoicacid, methyl ester

A mixture of the product from example 17 step (iii) (1.5 g)tetrabenzyltin (4.1 g) (Tetrahedron, 1993, 49, 9089) andtetrakis(triphenylphosphine) palladium (0) (0.35 g) in dry toluene (15ml) and dry dimethylformamide (7 ml) was heated at 105° C. for 72 hours.A further 0.4 g palladium catalyst was added and the mixture heated for72 hours. The mixture was partitioned between ethyl acetate and water.The organic phase was dried (MgSO₄) and evaporated. Purified bychromatography eluting with 25% ethyl acetate in toluene. Yield 0.28 g.

MS: APCI (+ve): 541 (M+1)

ii)5-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-[phenylmethyl]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (i) (0.28 g)by the method of example 6 step (iv). Purified by chromatography elutingwith 15% ethyl acetate in toluene. Yield 0.19 g.

1H NMR δ (DMSO) 12.62(s,1H), 7.67(d,1H), 7.56(d,2H), 7.50-7.10(m,13H),6.88(s,1H), 6.52(s,2H), 5.78(s,1H), 4.82(s,2H), 4.35(s,2H), 3.85(s,3H).

iii)5-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-[phenylmethyl]benzoicacid

the title compound was prepared from the product of step (ii) (0.2 g) bythe method of example 1 step (vi). Yield 0.12 g.

MS: APCI(+ve): 543 (M+1, 100%)

1H NMR δ (DMSO) 13.18(br s,1H), 12.63(s,1H), 7.70(d,1H), 7.56(d,2H),7.45-7.20(m,13H), 6.91(s,1H), 6.56(s,2H), 5.78(s,1H), 4.81(s,2H),4.40(s,2H).

MP: 135° C.

Example 192-Butyl-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

i)2-Butyl-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1-(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

The subtitle compound was prepared from the product of example 17 step(iii) (1.5 g) and tetra-n-butyltin (9 ml) by the method of example 18step (i). Purified by chromatography eluting with 30% ethyl acetate intoluene. Yield 0.6 g.

MS: APCI(+ve): 507 (M+1, 100%)

ii)2-Butyl-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

The subtitle compound was prepared from the product of example 17 step(iii) (1.5 g) and tetra-n-butyltin (9 ml) by the method of example 18step (i). Purified by chromatography eluting with 305 ethyl acetate intoluene. Yield 0.6 g.

MS: APCI(+ve): 507 (M+1, 100%)

iii)2-Butyl-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

The title compound was prepared from the product of step (ii) (0.4 g) bythe method of example 1 step (vi). Purified by reverse phase HPLC. Yield0.05 g.

MS: APCI(+ve): 509 (M+1, 100%)

1H NMR δ (DMSO) 13.10(br s,1H), 12.62(s,1H), 7.65(d,1H), 7.57(d,2H),7.40-7.20(m,8H), 6.94(s,1H), 6.70(s,2H), 5.80(s,1H), 4.80(s,2H),2.95(m,2H), 1.55(m,2H), 1.35(m,2H), 0.92(t,3H).

MP: 230° C.

Example 204-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]benzoicacid

i)4-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]benzoicacid, ethyl ester

A mixture of the product of example 2 step (ii) (1.5 g), potassiumcarbonate (1.71 g) and ethyl 4-fluorobenzoate (0.835 g) indimethylsulphoxide (20 ml ) was heated at 100° C. for 20 hours. Cesiumcarbonate(1.6 g) was added and the mixture heated at 100° C. for 5hours. The mixture was partitioned between ethyl acetate and water. Theorganic phase was dried (MgSO₄) and evaporated. Purified bychromatography 20-30% ethyl acetate in isohexane. Yield 0.72 g.

MS: APCI(+ve): 451 (M+1)

ii)4-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]benzoicacid, ethyl ester

The subtitle compound was prepared from the product of ste (i) (0.7 g)by the method of example 6 step (iv). Purified by chromatography elutingwith 20% ethyl acetate in isohexane. Used directly in the next step

MS: APCI(+ve): 467 (M+1, 100%)

iii)4-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]benzoicacid

The title compound was prepared from the product of step (ii) by themethod of example 1 step (vi). Purified by reverse phase chromatography.Yield 0.085%

MS: APCI(+ve): 439 (M+1, 100%)

1H NMR δ (DMSO) 13.20(br s,1H), 12.80(br s,1H), 8.04(d,2H), 7.66(d,2H),7.40(m,8H), 7.09(s,2H), 6.94(s,1H), 5.90(s,1H).

MP: 320° C.

Example 214-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl-1,3-bis[oxyaceticacid]

i) (±)-5-[[2H-3,4,5,6-Tetrahydropyran-2-yl]oxymethyl]benzene-1,3-diol

A mixture of 3,5-dihydrozybenzyl alcohol (10 g), dihydropyran (6.5 ml)and tosic acid (0.4 g) in dimethylformamide (50 ml) was stirred at rootemperature for 24 hours. The mixture was partitioned between ethylacetate and water. The organic phase was dried (MgSO₄and evaporated.Purified by chromatography eluting with 25% ethyl acetate i isohexane.Yield 12 g.

1H NMR δ (DMSO) 9.13(s,2H), 6.17(d,2H), 6.10(t,1H), 4.63(m,1H),4.48(d,1H), 4.26(d,1H), 3.75(m,1H), 3.45(m,1H), 1.70(m,2H), 1.5(m,4H).

ii)(±)-5-[[2H-3,4,5,6-Tetrahydropyran-2-yl]oxymethyl]phenyl-1,3-bis[oxyaceticacid], diethyl ester

A mixture of the product from step (i) (12 g) ethyl bromoacetate (26.7g) and potassium carbonate (27.8 g) in dry dimethylformamide (80 ml) wasstirred at room temperature of 5 hours and partitioned between ethylacetate and water. The organic phase was dried (MgSO₄) and evaporated.Purified by chromatography eluting with 15% ethyl acetate in isohexane.Yield 13.1 g.

1H NMR δ (CDCl₃) 6.57(d,2H), 6.42(t,1H), 4.71(d,1H), 4.66(m,1H),4.59(s,4H), 4.43(d,1H), 4.27(q,4H), 3.95-3.85(m,1H), 3.55(m,1H),2.00-1.50(m,6H), 1.33(t,6H).

iii) 5-[Hydroxymethyl]phenyl-1,3-bis[oxyacetic acid], diethyl ester

A solution of the product from step (ii) (13.1 g) in acetic acid (20ml), water (5 ml) and tetrahydrofuran (10 ml) was heated at 45° C. for24 hours. The solution was evaporated, azeotroped with toluene and theresidue purified by chromatography eluting with 30% ethyl acetate inisohexane. Yield 6 g.

MS: APCI(+ve): 313 (M+1)

iv) 5-[Bromomethyl]PHENYL-1,3-bis[oxyacetic acid], diethyl ester Amixture of the product from step (iii) (0.33g) and phosphoroustribromide (0.033 ml) in dry benzene (5 ml) was heated at reflux for 16hours. The supernatant was decanted and evaporated to give the product.Yield 0.35 g.

MS: CG-MS: 374/6 .

v)5-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]phenyl-1,3-bis[oxyaceticacid], diethyl ester

The subtitle compound was prepared from the product of step (iv) (1.02g) and example 2 step (ii) (0.75 g) by the method of example 7 step(ii). Purification was by chromatography eluting with 40% ethyl acetatein isohexane. Yield 1.04 g.

MS: APCI(+ve): 597 (M+1)

vi)5-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl-1,3-bis[oxyaceticacid], diethyl ester

The subtitle compound was prepared from the product of step (v) (1 g) bythe method of example 6 step (iv). Purification was by chromatographyeluting with 30% ethyl acetate in isohexane. Yield 0.7 g.

MS: APCI(+ve): 613 (M+1, 100%)

vii)5-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl-1,3-bis[oxyaceticacid]

The title compound was prepared from the product of step (vi) (0.7 g) bythe method of example 1 step (vi). Purified by reverse phase HPLC. Yield0.12 g.

MS: APCI(−ve): 555 (M−1, 100%)

1H NMR δ (DMSO) 7.56(d,2H), 7.35-7.21(m,6H), 6.86(s,1H), 6.69(s,2H),6.44(d,1H), 6.30(d,2H), 5.79(s,1H), 4.65(s,2H), 4.44(s,4H).

Example 224-[3-[Carboxymethoxy]-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]oxybutanoicacid

i) 2-[3-Hydroxy-5-[hydroxymethyl]phenyloxy]acetic acid, ethyl ester

the subtitle compound was prepared from 3,5-dihydroxybenzyl alcohol (5g) and ethyl bromoacetate (5.96 g) by the method of example 21 step(ii). Purified by chromatography eluting with 30% ethyl acetate inisohexane. Yield 1.6 g.

1H NMR δ (DMSO) 9.40(s,1H), 6.36(br s,1H), 6.30(br s,1H), 6.15(br s,1H),5.10(t,1H), 4.67(s,2H), 4.29(d,2H), 4.16(q,2H), 1.21(t,3H).

ii) 4-[3-[[Ethoxycarbonyl]methoxy]-5-[hydroxymethyl]phenyloxy]butanoicacid, ethyl ester

The subtitle compound was prepared from the product of step (i) (1.6 g)and ethyl 4-bromobutyrate (1.38 g) by the method of example 21 step(ii). Purified by chromatography eluting with 30% ethyl acetate intoluene. Yield 0.43 g.

1H NMR δ (CDCl₃) 6.55(br s,1H), 6.50(br s,1H), 6.40(br s,1H),4.62(d,2H), 4.30(q,2H), 4.12(q,2H), 3.98(t,2H), 2.49(t,2H), 2.10(m,2H),1.70(t,1H), 1.35-1.20(m,6H).

iii) 4-[3-Bromomethyl-5-[[ethoxycarbonyl]methoxy]phenyloxy]butanoicacid, ethyl ester

The subtitle compound was prepared from the product of step (ii) (0.42g) by the method of example 21 step (iv). Yield 0.47 g.

1H NMR δ (CDCl₃) 6.57(br s,1H), 6.51(br s,1H), 6.40(br s,1H),4.60(s,2H), 4.40(s,2H), 4.30(q,2H), 4.12(q,2H), 3.98(t,2H), 2.50(t,2H),2.13(m,2H), 1.35-1.20(m,6H).

iv)4-[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl)-3,4-dihydro-2,4-dioxo-1-(2H)-pryimidinyl]methyl]-5-[[ethoxycarbonyl]methoxy]phenyloxy]butanoicacid, ethyl ester

The subtitle compound was prepared from the product of step (iii) (0.45g) and example 2 step (ii) (0.38 g) by the method of example 7 step(ii). Purified by chromatography eluting with 30% ethyl acetate intoluene. Yield 0.5 g.

MS: APCI(+ve): 625 (M+1, 100%)

v)4-[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]5-[[ethoxycarbonyl]methoxy]phenyloxy]butanoicacid, ethyl ester

The subtitle compound was prepared from the product of step (iv) (0.47g) by the method of example 6 step (iv). Yield 0.32 g.

MS: APCI(+ve): 641 (M+1, 100%)

vi)4-[5-[Carboxymethoxy]-3-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyloxy]butanoicacid

The title compound was prepared from the product of step (v) (0.32 g) bythe method of example 1 step (vi). Yield 0.199 g.

MS: APCI(+ve): 558 (M+1, 100%)

1H, NMR: δ (DMSO) 12.60(s, 1H), 7.57(d, 2H), 7.40-7.20(m, 6H) 6.70(s,1H), 6.64(s,2H), 6.52(s, 1H), 6.39(s, 1H), 6.36(s, 1H), 5.80(s, 1H),4.70(br s, 4H), 3.95(t, 2H), 2.43(t, 2H), 1.95(m, 2H).

MP: 104-109° C.

Example 23

3-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl][carboxymethyl]amino]-3-thioxobutanoicacid

i) N-[3-Methylphenyl]glycine, ethyl ester

A mixture of m-toluidine (10 g), ethyl bromoacetate (10.3 ml), sodiumacetate (7.6 g) and water (5 ml in ethanol (50 ml) was stirred at roomtemperature overnight. The product was filtered off as the hydrobromidesalt. Yield 11.6 g.

1H NMR: δ (DMSO) 6.95(t, 1H) 6.39-6.31(m, 3H), 5.89(t, 1H), 4.10(q, 2H),3,85(d, 2H), 2.17(s, 3H), 1.19(t, 3H).

ii) 3-[[Ethoxycarbonylmethyl][3-methylphenyl]amino]-3-oxobutanoic acid,ethyl ester

The product of step (i) (2.74 g) was partitioned between ethyl acetateand saturated aqueous sodium bicarbonate. The organic phase was washedwith bicarbonate, dried (MgSO₄) and evaporated. The residue wasdissolved in diethyl ether (100 ml) and triethylamine (1.5 ml) wasadded. Ethyl succinyl chloride (1.6 ml) was added dropwise and themixture was stirred at room temperature for 2 hours, filtered andevaporated. Purified by chromatography eluting with 15% ethyl acetate inisohexane. Yield 2.63 g.

1H NMR: δ (CDCl₃) 7.27(m, 1H), 7.19(m, 3H), 4.34(s, 2H), 4.19(q, 2H),4.11(q, 2H), 2.60(t, 2H), 2.43(t, 2H), 2.37(s, 3H), 1.27(t, 3H), 1.24(t,3H).

iii)3-[[3-[Bromomethyl]phenyl][ethoxycarbonylmethyl]amino]-3-oxobutanoicacid, ethyl ester

A solution of the product from step (ii) (2.63 g) and N-bromosuccinimide(1.51 g) in ethyl acetate (80 ml) with catalytic azoisobutyronitrile wasirradiated under a 500 W halogen lamp for 6 hours. The mixture wasevaporated and the residue purified by chromatography eluting with10-20% ethyl acetate in isohexane. Yield 1.55 g.

1H NMR: δ (CDCl₃) 7.44-7.30(m, 4H), 4.49(s, 2H), 4.35(s, 2H), 4.20(q,2H), 4.11(q, 2H), 2.61(m, 2H), 1.27(t, 3H), 1.24(t, 3H).

iv)3-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]phenyl][ethoxycarbonylmethyl]amino]-3-oxobutanoicacid, ethyl ester

The subtitle compound was prepared from the product of step (iii) (1.2g) and example 2 step (ii) (0.8 g) by the method of example 7 step (ii).Purification was by chromatography eluting with 2% methanol indichloromethane. The product was then recrystallised from ethyl acetatein isohexane. Yield 1.18 g.

1H NMR: δ (DMSO) 11.24(s, 1H), 7.51(m, 3H), 7.40-7.16(m, 9H), 6.73(s,2H), 6.62(s, 1H), 5.31(s, 1H), 4.78(s, 2H), 4.90(q, 2H), 4.09(q, 2H),4.00(q, 2H), 2.45(m, 2H), 2.27(m, 2H), 1.17(t, 3H), 1.15(t, 3H).

v)3-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl][ethoxycarbonylmethyl]amino]-3-thioxobutanoicacid, ethyl ester

The subtitle compound was prepared from the product of step (iv) (1.18g) by the method of example 6 step (iv). Purification was bychromatography eluting with 5% ethanol in dicloromethane. Yield 0.6 g.

MS: APCI(+ve): 654 (M+1, 100%)

vi)3-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-3-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl][carboxymethyl]amino]-3-thioxobutanoicacid

The title compound was prepared from the product of step (v) (0.6 g) bythe method of example 1 step (vi). Yield 0.12 g.

MS: APCI(+ve): 598 (M+1, 100%)

1H NMR: δ (DMSO) 12.63(s, 1H), 7.59(m, 3H), 7.46(d, 1H), 7.39-7.19(m,8H), 6.95(s, 1H), 6.73(s, 2H), 5.81(s, 1H), 4.86(s, 2H), 4.83(br, s,2H),2.66(m, 2H), 2.66(m, 2H), 2.50(m, 2H).

MP: 175° C.

Example 24

N-[[3-[[5-{5H-Dibenzo[a,d]-cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-N-[phenylmethoxycarbonyl]glycine

i) N-[1,1-Dimethylethoxycarbonyl]glycine, methyl ester

Di-tert-butyldicarbonate (9.8 g) was added to a suspension of glycinemethyl ester hydrochloride (5 g) and triethylamine (7 ml) intetrahydrofuran (60 ml). The mixture was stirred at room temperature for18 hours and partitioned between ethyl acetate and 2M HCl. The organicphase was dried (MgSO₄) and evaporated. Purified by chromatographyeluting with 20-30% ethyl acetate is isohexane. Yield 7.43 g.

1H NMR: δ (CDCl₃) 5.03 (br s, 1), 3.92(d, 2H), 3.76(s, 3H), 1.46(s, 9H).

ii)N-[[3-[Bromomethyl]phenyl]methyl]-N-[1,1-dimethylethoxylcarbonyl]glycine,methyl ester

A solution of the product from step (i) (5 g) in tetrahydrofuran (10 ml)was added dropwise to a suspension of sodium hydride (1.1 g) intetrahydrofuran (40 ml) at 0° C. The mixture was warmed to roomtemperature and stirred for 30 minutes then added dropwise to a solutionof α,α′-dibromo-m-xylene (10.56 g) in tetrahydrofuran (40 ml). Themixture was stirred at room temperature for 2 hours, quenched withaqueous ammonium chloride and partitioned between ethyl and acetate andwater. The organic phase was dried (MgSO₄) and evaporated. Purified bychromatography eluting with 10% ethyl acetate in isohexane. Yield 2.8 g.

1H NMR δ (CDCl₃) 7.32-7.15(m, 4H), 4.54+4.50(2H, rotamers, 4.48(s, 2H),3.95+3.80(2H, rotamers), 3.71(s, 3H), 1.47(s, 9H).

iii)N-[[3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-N-[1,1-dimethylethoxycarbonyl]glycine,methyl ester

The subtitle compound was prepared from the product of step (ii) (2.08 )and example 2 step (ii) (1.75 g) by the method of example 7 step (ii).Purified by chromatography eluting with 50% ethyl acetate in isohexane.Yield 1.8 g.

1H NMR: δ (DMSO) 11.21 (s, 1H), 7.52-7.23(m, 10H), 7.06(s, 2H),6.67+6.65(2xs, 2H, rotamers), 6.56(s, 1H), 5.29(s, 1H), 4.72(s, 2H),4.47+4.41(2xs, 2H, rotamers), 3.95+3.87(2xs, 2H, rotamers),3.65+3.64(2xs, 3H, rotamers), 1.38+1.30(2xs, 9H, rotamers).

iv)N-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]glycine,methyl ester

A solution of the product of step (iii) (1.8 g) in trifluoroacetic acid(5 ml) and dichloromethane (30 ml) was stirred overnight at roomtemperature. Toluene was added and the mixture was evaporated. Theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The organic phase was dried (MgSO₄) and evaporated.

MS: APCI(+ve): 494 (M+1)

v)N-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-N-[phenylmethoxycarbonyl]glycine,methyl ester

Benzyl chloroformate (0.145 ml) was added to a solution of the productof step (iv) (0.44 g) and triethylamine (0.17 ml) in dichloromethane (10ml). The mixture was stirred at room temperature for 2 hours. Furtheraliquots of benzyl chloroformate (0.1 ml) and triethylamine (0.3 ml)were added after 2 and 4 hours. The mixture was stirred overnight andpartitioned between ethyl acetate and water. The organic phase was dried(MgSO₄), evaporated and purified by chromatography eluting with 60%ethyl acetate in isohexane.

Yield 0.47 g.

1H NMR: δ (CDCl₃) 7.97(s, 1H), 7.51-6.95(m, 3H), 5.31(s, 1H), 5.23(d,2H), 4.68-4.59(m, 4H), 3.97+3.87(2xs, 2H, rotamers), 3.70+3.65(2xs, 3H,rotamers).

vi)N-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-N-[phenylmethoxycarbonyl]glycine,methyl ester

The subtitle compound was prepared from the product of step (v) (0.46 g)by the method of example 6 step (iv). Yield 0.4 g.

MS: APCI(+ve): 644 (M+1)

vii)N-[[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-N-[phenylmethoxycarbonyl]glycine

The title compound was prepared from the product of step (vi) (0.39 g)by the method of example 1 step (vi). Yield 0.15 g.

MS: APCI(+ve): 630 (M+1)

1H NMR: δ (DMSO) 12.86(br s, 1H), 12.62(s, 1H), 7.57(d, 2H),7.43-7.10(m, 15H), 6.88+6.84(2xs, 1H, rotamers), 6.63+6.56(2xs, 2H,rotamers), 5.79(s, 1H), 5.15+5.12(2xs, 2H, rotamers), 4.78+4.73(2xs, 2H,rotamers), 4.55(s, 2H), 3.93(s, 2H).

MP: 120° C.

Example 25

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[[carboxymethyl][diphenylmethyl]amino]benzoicacid

i) 3-[Chlorocarbonyl]-5-nitrobenzoic acid, methyl ester

A mixture of methyl hydrogen-5-nitroisophthalate (50 g) and thionylchloride (75 ml) was heated of reflux overnight, cooled and evaporated.The residue was recrystallised from light petroleum (b.p. 40-60° C.) anda trace of ethyl acetate. Yield 50 g. Used directly in the next step.

ii) 3-[Hydroxymethyl]-5-nitrobenzoic acid, methyl ester

A stirred solution of the product from step (i) (46.54 g) and sodiumborohydride (13.01 g) in 1,4-dioxane (200 ml) was heated at reflux for17 hours. The mixture was cooled and treated with triethylamine (27.9ml), poured onto ice-water and extracted with ethyl acetate. Thecombined extracts were dried (MgSO₄) and evaporated. The product wasrecrystallised from isohexane. Yield 19.38 g.

1H NMR: δ (CDCl₃) 8.76(t, 1H), 8.57(d, 1H), 8.45(s, 1H), 4.89(s, 2H),3.99(s, 3H).

iii) 3-Amino-5-[hydroxymethyl]benzoic acid, methyl ester

A mixture of the product from step (ii) (23.4 g), ammonium chloride (23g) and iron powder (23 g) in methanol (200 ml) and water (200 ml) washeated at reflux for 1 hour. The mixture was filtered and concentratedunder reduced pressure and the residue treated with saturated aqueoussodium bicarbonate and extracted with ethyl acetate. The extract wasdried (MgSO₄) and evaporated. Yield 19.38 g.

MG: GC-MS: 181 (M⁺)

iv) 3-[[Ethoxycarbonylmethyl]amino]-5-[hydroxymethyl]benzoic acid,methyl ester

The subtitle compound was prepared from the product of step (iii) (10 g)by the method of example 22 step (i). Purified by chromatography elutingwith 50% ethyl acetate in isohexane. Yield 9.98 g.

MS: APCI(+ve): 268 (M+1, 100%)

v)3-[[Ethoxycarbonylmethyl][diphenylmethyl]amino]-5-[hydroxymethyl]benzoicacid, methyl ester

A mixture of the product from step (iv) (3 g), potassium carbonate(15.48 g) and bromodiphenylmethane (2.77 g) in dimethylformamide (100ml) was heated at 50° C. for 24 hours. The mixture was partitionedbetween ethyl acetate and brine. The organic phase was dried (MgSO₄) andevaporated. Purified by chromatography eluting with 30% ethyl acetate inisohexane. Yield 0.51 g.

MS: APCI(+ve): 434 (M+1)

vi)3-Chloromethyl-5-[[ethoxycarbonylmethyl][diphenylmethyl]amino]benzoicacid, methyl ester

The product of step (v) (0.5 g) in tetrahydrofuran (20 ml) was treatedwith triphosgene (0.114 g) then pyridine (0.183 g). After 16 hours thereaction was evaporated and purified by chromatography eluting with 20%ethyl acetate in isohexane. Yield 0.4 g.

MS: APCI(+ve): 452 (M+1)

vii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1-(2H)-pyrimidinyl]methyl]-5-[[ethoxycarbonylmethyl][dipehenylmethyl]amino]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (vi) (0.4 g)and example 2 step (ii) (1.75 g) by the method of example 2 step (iii).Purified by chromatography eluting with 20% ethyl acetate in toluene.Yield 0.49 g.

MS: APCI(+ve): 718 (M+1)

vii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[[ethoxycarbonylmethyl][diphenylmethyl]amino]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (vii) (0.49g) by the method of example 6 step (iv). Purified by chromatographyeluting with 20% ethyl acetate in toluene. Yield 0.26 g. Used directlyin the next step.

viii)3[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[[ethoxycarbonylmethyl][diphenylmethy]amino]benzoicacid, methyl ester The subtitle compound was prepared from the productof step (vii) (0.49 g) by the method of example 6 step (iv). Purified bychromatography eluting with 20% ethyl acetate in toluene. Yield 0.26 g.Used directly in the next step.

ix)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl][diphenylmethyl]amino]benzoicacid

The title compound was prepared from the product of step (viii) (0.26 g)by the method of example 1 step (vi). Yield 0.16 g.

MS: APCI(+ve): 692 (M+1)

1H NMR: δ (DMSO) 12.95(br s, 1H), 12.55(br s, 1H), 12.40-11.00(br s,1H), 7.60(d, 2H), 7.40-7.20(m, 17H), 7.10(s, 1H), 6.94(br s, 1H),6.81(s, 1H), 6.80(s, 2H), 6.22(s, 1H), 5.80(s, 1H), 4.75(s, 2H), 4.00(s,2H).

MP: 210° C.

Example 26

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[carboxymethylamino]benzoicacid

A mixture of the methyl ester of3-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[carboxymethylamino]benzoicacid (by-product from example 25 step (viii) (0.041 g) and lithiumhydroxide (0.011 g) in methanol (5 ml) and water (5 ml) was stirred atroom temperature for 3 days and heated at 50° C. for 24 hours. Themixture was concentrated under reduced pressure and purified by reversephase HPLC. Yield 28 mg.

MS: APCI(+ve): 526 (M+1, 100%)

Example 27

2-[2-5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid

i) 2-[2-Bromoethoxy]benzoic acid, methyl ester

The subtitle compound was prepared from methyl salicylate (5 g) and1,2-dibromoethane (30.67 g) by the method of example 21 step (ii).Purified by chromatography eluting with 10% ethyl acetate in isohexane.Yield 4.9 g.

1H NMR: δ (CDCl₃) 7.81(dd, 1H), 7.48(ddd, 1H), 7.04(dt, 1H), 6.98(br d,1H), 4.37(t, 2H), 3.90(s, 3H), 3.70(t, 2H).

ii)2-[2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid, methyl ester

The subtitle compound was prepared from the products of step (i) (0.86g) and example 2 step (ii) (1 g) by the method of example 2 step (iii).Purified by chromatography eluting with 40% ethyl acetate in toluene.Yield 0.41 g.

MS: ESI(+ve): 480 (M⁺)

iii)2-[2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (ii) (0.4 g)by the method of example 5 step (iii). Recrystallised from toluene.Yield 0.09 g.

MS; APCI(+ve): 497 (M+1)

iv)2-[2-5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoic acid

The title compound was prepared from the product of step (iii) (0.087 g)by the method of example 1 step (vi). Yield 0.014 g.

1H NMR: δ (DMSO) 12.61(s, 1H), 12.55(br s, 1H), 7.70(d, 1H), 7.60(d,2H), 7.50(t, 1H), 7.40−7.20(m, 7H), 7.09(m, 2H), 6.82(s, 2H), 5.85(s,1H), 4.21(t, 2H), 4.01(t, 2H).

Example 28

2-[Carboxymethoxy]-6-2-5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid

i) 2,6-Dihydroxybenzoic acid, methyl ester

The subtitle compound was prepared from 2,6-dihydroxybenzoic acid (25 g)by the method of example 17 step (i). Yield 10.33 g. Used directly inthe next step.

ii) 2-Hydroxy-6-[methoxycarbonylmethoxy]benzoic acid, methyl ester

The subtitle compound was prepared from the product of step (i) (10 g)and methyl bromacetate (5.5 ml) by the method of example 11 step (i).Purified by chromatography eluting with 20% ethyl acetate in isohexane.Yield 3.68 g.

1H NMR: δ (CDCl₃) 11.51(s, 1H), 7.33(t, 1H), 6.67(d, 1H), 6.30(d, 1H),4.67(s, 2H, 3.97(s, 3H), 3.82(s, 3H).

iii) 2-[2-Bromoethoxy]-6-methoxycarbonylmethoxy]benzoic acid, methylester

The subtitle compound was prepared from the product of step (ii) (3.6 g)and 1,2-dibromoethane (5.17 ml) by the method of example 21 step (ii).Purified by chromatography eluting with 20% ethyl acetate in isohexane.Yield 3.2 g.

1H NMR: δ (CDCl₃) 7.29(t, 1H), 6.60(d, 1H), 6.48(d, 1H), 4.66(s, 2H),4.31(t, 2H), 3.98(s, 3H), 3.80(s, 3H), 3.60(t, 2H).

iv)2-[2-5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1-(2H)-pyrimidinyl]ethoxy]-6-[methoxycarbonylmethoxy]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (iii) (1.44g) and example 2 step (ii) (1.25 g) by the method of example 2 step(iii). Purified by chromatography eluting with 30% ethyl acetate intoluene. Yield 0.83 g. Used directly in the next step.

v)2-[2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]-6-[methoxycarbonylmethoxy]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (iv) (0.83g) by the method of example 6 step (iv). Purified by chromatographyeluting with 30% ethyl acetate in toluene.

Yield 0.19 g. Used directly in the next step.

vi)3-[2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]-2-[methoxycarbonyl]phenoxyaceticacid, methyl ester

The subtitle compound was prepared from the product of step (v) (0.19 g)by the method of example 1 step (vi). Purified by reverse phasechromatography. Yield 0.092 g.

MS: APCI(+ve): 571 (M+1)

vii)2-[Carboxymethoxy]-6-[2-[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid

A mixture of the product from step (vi) (0.073 g) and sodium hydroxide(1 g) in methanol (20 ml) and water (20 ml) was heated at 60° C.overnight. The mixture was acidified with 2M HCl and extracted withethyl acetate. The extract was evaporated and the residue purified byreverse phase chromatography. Yield 0.04 g.

MS: APCI(+ve): 557 (M+1)

1H NMR: δ (DMSO) 12.95(br s, 1H), 12.60(br s, 1H), 7.60(d, 2H),7.40−7.20(m, 7H), 7.05(br s, 1H), 6.89(s, 2H), 6.60(d, 2H), 5.83(s, 1H).

MP: 187° C.

Example 29

4-[2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]-1,3-benzenedioicacid

i) 4-Hydroxy-1,3-benzenedioic acid, dimethyl ester

A mixture of 4-hydroxyisophthalic acid (25 g) and trimethylsily chloride(100 ml) in methanol (200 ml) was heated at reflux for 4 hours. Themixture was evaporated and partitioned between ethyl acetate and aqueoussodium bicarbonate. The organic phase was dried (MgSO₄) and evaporated.Yield 25.67 g. Used directly in the next step.

ii) 4-[2-Bromoethoxy]-1,3-benzenedioic acid, dimethyl ester

A mixture of the product of step (i) (5 g) and potassium carbonate(13.14 g) in dimethylformamide (100 ml) was treated with1,2-dibromoethane (8.2 ml) and stirred overnight at room temperature.The mixture was partitioned between ethyl acetate and water. The organicphase was dried (MgSO₄) and evaporated. Purified by chromatographyeluting with 20% ethyl acetate in isohexane. Yield 4.6 g.

1H NMR: δ (CDCl₃) 8.49(s, 1H), 4.44(t, 2H), 3.95(s, 6H), 3.70(t, 2H).

iii) 4-2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]ethoxy]-1,3-benzenedioicacid, dimethyl ester

The subtitle compound was prepared from the product of step (ii) (1.31g) and example 2 step (ii) (1.25 g) by the method of example 2 step(iii). Yield 0.83 g. Used directly in the next step.

iv)4-2-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]-1,3-benzenedioicacid, dimethyl ester

The subtitle compound was prepared from the product of step (iii) (0.81g) by the method of example 6 step (iv). Purified by chromatographyeluting with 40% ethyl acetate in dichloromethane. Yield 0.34 g. Useddirectly in the next step.

v)4-[2-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]-1,3-benzenedioicacid

The title compound was prepared from the product of step (iv) (0.33 g)by the method of example 1 step (vi). Purified by reverse phasechromatography. Yield 0.095 g.

MS: APCI(+ve): 527 (M+1)

1H NMR: δ](DMSO) 12.88(br s, 1H), 12.61(s, 1H), 8.27(s, 1H), 8.05(d,1H), 7.60(d, 2H), 7.30(m, 9H), 7.10(br s, 1H), 6.83(s, 2H), 5.84(s, 1H),4.32(m, 2H), 4.04(m, 2H).

MP: 284° C.

Example 30

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dithioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

i)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-4-methylthio-2-oxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

A mixture of the product from example 2 step (iv) (1 g), sodiumbicarbonate (0.22 g) and methyl iodide (0.7 ml) in water (4 ml) andmethanol (30 ml) was heated at 40° C. for 4 hours. The mixture wasconcentrated under reduced pressure and partitioned between ethylacetate and water. The organic phase was dried (MgSO₄) and evaporated.Used directly in the next step.

ii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-4-methylthio-2-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

The subtitle compound was prepared from the product of step (i) by themethod of example 1 step (v) using benzene as solvent. Purified bychromatography eluting with 8% ethyl acetate in toluene. Yield 0.6 g.

1H NMR: δ (DMSO) 7.98(d, 1H), 7.78(s, 1H), 7.67(d, 2H), 7.59(t, 1H),7.53(d, 1H), 7.45-7.40(m, 2H), 7.35-7.30(m, 4H), 6.82(s, 1H), 6.62(s,2H), 5.55(s, 2H), 5.47(s, 1H), 3.94(s, 3H), 2.36(s, 3H).

iii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5yl}-3,4-dihydro-2,4-dithioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, methyl ester

Hydrogen sulphide gas was bubbled through a solution of the product fromstep (ii) (0.3 g) in triethylamine (10 ml) and pyridine (40 ml) at roomtemperature for 2 hours. The mixture was evaporated. Purified bychromatography eluting with 8% ethyl acetate in toluene.

Yield 0.28 g.

1H NMR: δ (DMSO) 13.73(s, 1H), 8.00(m, 1H), 7.85(s, 1H), 7.65-7.55(m,3H), 7.40−7.30(m, 1H), 7.30-7.20(m, 6H), 6.97(s, 1H), 6.57(s, 2H),5.97(s, 1H), 5.75(s, 1H), 5.41(s, 2H), 3.93(s, 3H).

iv)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dithioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

The title compound was prepared from the product of step (iii) (0.28 g)by the method of example 1 step (vi). Yield 0.21 g.

MS: APCI(+ve): 469 (M+1, 100%)

1H NMR: δ (DMSO) 13.73(s, 1H), 13.18(br s, 1H), 8.00(d, 1H), 7.83(s,1H), 7.70−7.50(m, 4H), 7.40-7.30(m, 2H), 7.30-7.20(m, 4H), 6.90(s, 1H),6.60(s, 2H), 5.40(s, 2H).

MP: 167-170° C.

Example 31

3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-4-oxo-2-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

i) 3-Methylbenzoic acid, [1,1-dimethylethyl] ester

To a solution of tert-butanol (12.2 ml) in tetrahydrofuran (300 ml) at0° C. was added n-butyllithium (52 ml) dropwise over 10 minutes.m-Toluoyl chloride (20 g) was added and the mixture heated at reflux for1 hours. The mixture was partitioned between ethyl acetate and water andthe organic phase dried (MgSO₄) and evaporated. Purified bychromatography eluting with 20% dichloromethane in isohexane. Yield14.78 g. Used directly in the next step.

ii) 3-[Bromomethyl]benzoic acid, [1,1-dimethylethyl] ester

The subtitle compound was prepared from the product of step (i) (14.78g) by the method of example 23 step (iii). Purified by chromatographyeluting with 10% ethyl acetate in isohexane. Yield 12.35 g.

1H NMR: δ (CDCl₃) 7.99(s, 1H), 7.93(d, 1H), 7.54(d, 1H), 4.52(s, 2H),1.60(s, 9H).

iii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, [1,1-dimethylethyl] ester

The subtitle compound was prepared from the product of step (ii) (4.3 g)and example 2 step (ii) (1.25 g) by the method of example 7 step (ii).Purified by chromatography eluting with 25% ethyl acetate in toluene.Yield 5.25 g.

1H NMR: δ (DMSO) 11.26(brs, 1H), 7.90(d, 1H), 7.72(s, 1H), 7.52(d, 2H),7.50-7.20(m, 6H), 6.70(s, 2H), 6.68(brs, 1H), 5.31(s, 1H), 4.80(s, 2H),1.58(s, 9H).

iv)3-[[5-{5-H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, [1,1]-dimethylethyl] ester

The subtitle compound was prepared from the product of step (iii) (2 g)by the method of example 6 step (iv). Purified by chromatography elutingwith 30% ethyl acetate in toluene.

Yield 1.96 g. Used directly in the next step.

v)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-4-methylthio-2-oxo-1(2H)-pyrimidinyl]methyl]benzoicacid, [1,1-dimethylethyl] ester

The subtitle compound was prepared from the product of step (iv) (0.5 g)by the method of example 30 step (i). Yield 0.46 g.

1H NMR: δ (CDCl₃) 8.03(m, 1H), 7.77(s, 1H), 7.50-7.10(m, 9H), 6.47(s,1H), 6.53(s, 2H), 4.87(s, 2H), 5.20(s, 1H), 2.44(s, 3H), 1.66(s, 9H).

vi)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-4-methylthio-2-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, [1,1-dimethylethyl] ester

A mixture of the product from step (v) (0.46 g) and Lawesson's reagent(0.18 g) in benzene (5 ml) was heated at reflux for 2 hours. The mixturewas evaporated and purified by chromatography eluting with 10% ethylacetate in toluene. Yield 0.5 g.

MS: APCI(+ve): 539 (M+1, 100%)

vii)3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-4-oxo-2-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid

A solution of the product from step (vi) (0.5 g) in dichloromethane (12ml) was treated with trifluoracetic acid (9 ml) and stirred at roomtemperature for 3.5 hours. The mixture was evaporated and the residuedissolved in ethanol (50 ml) and 2M HCl. The mixture was heated atreflux at 4 hours. The mixture was evaporated and the residue treatedwith water, filtered and dried (MgSO₄). Purified by chromatographyeluting with 5% methanol in dichloromethane. Yield 0.27 g.

MS: APCI(−ve): 451 (M−1, 100%)

¹H NMR: δ (DMSO) 13.18(br s, 1H), 12.60(br s, 1H), 7.97(d, 1H), 7.78(s,1H), 7.60-7.20(m, 10H), 6.73(s, 1H), 6.62(s, 2H), 5.39(s+s, 3H).

MP: 258° C.

PHARMACOLOGICAL DATA

The following example describes the assay used to determine how stronglythe compounds of the invention bind to P-2-purinoceptor 7-TM G-proteincoupled receptors. The assay used a human P2Y2 receptor clone which wasisolated from HL60 cells cDNA and then stably transfected into a Jurkatcell line (using methods described in “Cloning and Characterisation of aBovine P_(2Y) Receptor” Henderson et al (1995), 212, 2, 648-656; Parr etal Proc. Natl. Acad. Sci USA (1994), 91, 3275-3279 and Proc Natl AcadSci USA (1994), 91, 13067). The cloned receptor mediates an increase inintracellular calcium in the cell line, which possesses no endogenuousnucleotide receptor of its own.

The transfected Jurkat cells were maintained at a concentration of fromabout 1×10⁵ to 10×10⁵ cells/ml in RPMI containing 4% heat inactivatedbovine serum, 2% penicillin/streptomycin and 1% glutamine. The cellswere incubated at 37° C. in an atmosphere of air with 5% CO₂.

The cells were spun down at r.p.m. for 5 minutes and resuspended in 10ml basal salt solution (BSS) containing 125 mM of NaCl, 5 mM of KCl, 1mM of MgCl, 1.5 mM of CaCl₂, 25 mM of HEPES, 5 mM of glucose and 1 mg/mlof bovine serum albumin, having a pH of 7.3. The concentration of cellswas determined using a Technicon cell counter. From 0.75×10⁸ to 1×10⁸cells were spun down, resuspended to a concentration of 3.3×10⁷ cells/mlin BSS and incubated with either 17 μM fluo-3AM or 17 μM Fura-2AM at 37°C. for 35 minutes with vigorous shaking. The dye used was dependent uponthe fluorescence and absorption properties of the compounds of theinvention. In general for compounds of formula (I) wherein Q¹ representsa S atom, fluo-3AM was used and for compounds wherein Q¹ represents an Oatom, either fluo-3AM or fura-2 AM were used. The cells were again spundown and washed once with the same volume of BSS before beingresuspended in BSS to a concentration of 1×10⁶ cells/ml ready fortesting.

When fluo-3AM was used as the dye, the cell solution was left at roomtemperature to recover for approximately 30 minutes before testing.

Fura-3AM loaded cells were divided into aliquots of about 10 ml and werewarmed to 37° C. for 10 minutes before testing.

Calcium response were measured on a SPEX Fluomax using 508 nm excitationand 525 nm emission wavelengths at room temperature for Fluo-3 AM loadedcells and 340/380 nm excitation and 510 nm emission wavelengths forFura-2 AM loaded cells. Each cuvette contained 2 ml of cells and wasstirred at high speed throughout the test. Basal fluorescence wasmeasured for 5 seconds before 20 μl of a 10⁻²-10⁻⁶ M solution of thetest compound in water was added to the 2 ml solution of the cells. Theresponse was calibrated by the addition of Triton-X-100 (68 μl, 10%solution) and then EGTA (180 μl, 0.5 M solution). For each compound theresponse was compared to that of UTP.

The compounds exemplified have pA2 values greater than 4.0.

What is claimed is:
 1. A compound of formula I:

in which: X is a bond, CH₂ or a C₁₋₃alkylene group optionallyinterrupted by oxygen; R is hydrogen, NO₂, NH₂, N(C₁₋₆alkyl)₂, CO₂H,CH₂OH, halogen, CO₂C₁₋₆alkyl, C₁₋₈alkyl optionally interrupted by one ormore oxygen, nitrogen or sulphur atoms and optionally substituted byCO₂H or R is hydroxy, phenyl optionally substituted by CH₂CO₂H, orCONR³R⁴ where R³ and R⁴ are independently hydrogen, C₁₋₆alkyl optionallysubstituted by hydroxy or CO₂H and/or optionally interrupted by oxygen,nitrogen or sulphur; R¹ is NR⁵R⁶ or CH₂NR⁵R⁶ where R⁵ and R⁶ areindependently hydrogen, CH₂CO₂H, CHPh₂ or C(═S)CH₂CH₂CO₂H, or R¹ isCH₂NR⁷CH₂CO₂H where R⁷ is hydrogen, C₁₋₆ alkyl or CO₂CH₂PH, or R¹ isC₁₋₈alkyl optionally interrupted by one or more oxygen, nitrogen orsulphur atoms and optionally substituted by CO₂H, or R¹ is —R⁸—PO(OH)₂,or —R⁸-tetrazol-5-yl where R⁸ is a bond, OCH₂, SCH₂, CONH, CONHCH₂,CONHCH₂CONH, NHCH₂CONH, NHCH(R³), NR⁹(CH₂)q where R⁹ is hydrogen orC₁₋₆alkyl and q is 1 or 2 or R²⁰—CO₂H where R²⁰ is a bond, CONHCH₂ orNHCH(R³) where R³ is as defined above, or R¹ is a group of formula (i):

where B is a 4-, 5-, or 6-membered saturated ring containing a nitrogenatom optionally substituted by hydroxy and substituted by CO₂H orCONH-Het where Het is tetrazol-5-yl, or a thiazole or thiadiazole ringsubstituted by CO₂H or CH₂CO₂H, or B is phenyl or a 5-membered aromaticheterocylic ring containing 1 to 3 heteroatoms selected from nitrogen,oxygen or sulphur optionally substituted by one or more groups selectedfrom CF₃, CO₂H, CH₂OH, C₁₋₆alkyl optionally interrupted by one or moreoxygen atoms, CH₂CH₂CO₂H, C(CO₂H)═N—OMe, tetrazol-5-yl orCH₂tetrazol-5-yl; and R¹⁰ is a bond, sulphur atom, —CONH—, CH₂, CH₂O, agroup —NR¹¹—CH(CO₂H)—CH₂—, or a group or —NR¹¹—(CH₂)_(p—)CONR¹²—whereR¹¹ and R¹² are independently hydrogen or C₁₋₆alkyl and p is 1 or 2; R²is a group of formula (ii) or (iii):

where R¹³ groups are independently hydrogen, halogen, methoxy,methylthio or C₁₋₂alkyl (optionally substituted by one or more fluorineatoms); R¹⁴ groups are independently hydrogen, halogen, hydroxy,C₁₋₃alkylthio, C₁₋₄alkyl (optionally substituted by one or more fluorineatoms, C₃₋₄ cycloalkyl, MeOCH₂, MeSCH₂ or C₁₋₂alkoxy; R¹⁵ groups areindependently hydrogen, halogen or methyl (optionally substituted by oneor more fluorine atoms); Z¹ is CH═CH, CF═CH or CF═CF; Z² is a singlebond, oxygen, sulphur, CH₂CH═CH, CH₂CH═CHCH₂ or a C₁₋₄alkylene groupoptionally interrupted by an oxygen or sulphur atom; R¹⁶ areindependently hydrogen, halogen, C₁₋₂alkyl, CF₃ or a methylthio group orhydroxy; Q¹ and Q² each independently represent an O or S; or a saltthereof, provided that when Q¹ is oxygen, R² is a group of formula (ii).2. A compound according to claim 1 in which X is CH₂, a bond or CH₂CH₂O.3. A compound according to claim 1 in which R is hydrogen, C₁₋₆alkoxy,C₁₋₈alkyl optionally interrupted by one or two oxygen atoms andoptionally substituted by CO₂H, CH₂OH, hydroxy and halogen.
 4. Acompound according to claim 1 in which R¹ is CO₂H, —PO(OH)₂, C₁₋₈alkyloptionally interrupted by one or two oxygen atoms and optionallysubstituted by CO₂H, or R¹ is a group of formula (i) where B is phenyl,thiazole, pyrazole optionally substituted by CO₂H or C₁₋₆alkyloptionally interrupted by one or two oxygen atoms, or R¹ is NR⁵R⁶ orCH₂NR⁵R⁶ where R⁵ and R⁶ are independently, CH₂CO₂H, CHPh₂ orC(═S)CH₂CH₂CO₂H—, or R¹ is CH₂NR⁷CH₂CO₂H where R⁷ is CO₂CH₂Ph.
 5. Acompound according to claim 1 in which R² is a group of formula (ii)where Z¹ is CH═CH.
 6. A compound according to claim 1 in which Q¹ is Sand Q² is O or S.
 7. A compound according to claim 1 which is:3-[[5-[9H-Fluoren-9-yl]-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzeneaceticacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzenephosphonicacid,5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-methoxybenzoicacid,2-[3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1-(2H)-pyrimidinyl]methyl]phenyl]-4-thiazolecarboxylicacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[2-methoxyethoxymethyl]benzoicacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[phenoxymethyl]benzoicacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[ethoxymethyl]benzoicacid,1-[[3-[[3-Carboxy-5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-4-pyrazolecarboxylicacid,3-[[3-[[3-Carboxy-5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-5-ethoxybenzoicacid,3-[[3-Carboxy-5-[[5-{5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methoxy]-5-[2-methoxyethoxy]benzoicacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[hydroxymethyl]benzoicacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[methylbenzoicacid,5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-hydroxybenzoicacid,3-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenoxy]aceticacid,2-Bromo-5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-2-[phenylmethyl]benzoicacid,2-Butyl-5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,4-[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]benzoicacid,5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl-1,3-bis[oxyaceticacid],4-[3-[Carboxymethoxy]-5-[[5-{5H-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]oxybutanoicaid,3-[[3-[[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl][carboxymethyl]amino]-3-thioxobutanoicacid,N-[[3-[[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]phenyl]methyl]-N-[phenylmethoxycarbonyl]glycine,3-[[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[[carboxymethyl][diphenylmethyl]amino]benzoicacid,3-[[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-5-[carboxymethylamino]benzoicacid2-[2-[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid,2-[Carboxymethoxy]-[6-[2-[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]benzoicacid,4-[2-[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]ethoxy]-benzenedioicacid,3-[[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid,3-[[5-{5-Dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]benzoicacid, or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a compound of formula I or a salt or solvatethereof as defined in claim 1 in association with a pharmaceuticallyacceptable adjuvant, diluent or carrier.
 9. A process for thepreparation of compounds of formula I as defined in claim 1 whichcomprises: reacting a compound of formula (II):

where Q¹, Q² and R² are defined in formula (I) or are protectedderivatives thereof with a compound of formula (III):

where R, R¹ and X are defined in formula (I) or are protectedderivatives thereof and L is a leaving group, and optionally thereafterin any order: removing any protecting groups forming a salt.
 10. Amethod of treating an inflammatory condition, which comprises the stepof administering to a patient in need of such treatment an effectiveamount of a compound of formula (I) as defined in claim
 1. 11. A methodaccording to claim 10, wherein said compound of formula (I) isco-administered with another anti-inflammatory agent.